Substituted oxindole derivatives and their use as vasopressin receptor ligands

ABSTRACT

The present invention relates to novel oxindole derivatives of the general formula (I) to medicaments comprising them and to their use for the prophylaxis and/or treatment of diseases vasopressin dependent.

The present invention relates to novel substituted oxindole derivatives,to medicaments comprising them and to their use for treating diseases.

Vasopressin is an endogenous hormone which exerts widely diverse effectson organs and tissues. It is suspected that the vasopressin system isinvolved in various pathological states such as, for example, heartfailure and high blood pressure. At present three receptors (V1a, V1b orV3 and V2) via which vasopressin mediates its numerous effects areknown. Antagonists of these receptors are therefore being investigatedas possible novel therapeutic approaches to the treatment of diseases(M. Thibonnier, Exp. Opin. Invest. Drugs 1998, 7(5), 729-740).

The present application describes novel substituted oxindoles carryingan arylsulphonyl group in position 1.1-Phenylsulphonyl-1,3-dihydro-2H-indol-2-ones have previously beendescribed as ligands of vasopressin receptors. WO 93/15051, WO95/18105,WO 98/25901, WO 01/55130, WO 01/55134, WO 01/64668 and WO 01/98295describe derivatives derived from the oxindole skeleton and havingarylsulphonyl groups in position 1. These compounds differ essentiallyin the substitution in position 3.

In particular, WO 93/15051 and WO 98/25901 describe1-phenylsulphonyl-1,3-dihydro-2H-indol-2-ones in which the oxindolestructure is substituted in position 3 by two alkyl radicals which mayalso together form a cycloalkyl radical (spiro linkage) as ligands ofvasopressin receptors. Alternatively, the spiro ring may compriseheteroatoms, such as oxygen and nitrogen (optionally with substituents).

WO 95/18105 describes 1-phenylsulphonyl-1,3-dihydro-2H-indol-2-oneshaving a nitrogen atom in position 3 as ligands of vasopressinreceptors. In addition, radicals which are selected from the groupconsisting of alkyl, cycloalkyl, phenyl and benzyl are attached inposition 3 (in each case optionally with substituents).

WO 03/008407 describes 1-phenylsulphonyloxindoles in whichpyridylpiperazines are attached via an oxycarbonyl group to the oxindolein position 3.

WO 2005/030755 describes as Example 108, the carbamate compound4-(1-methylpiperidin-4-yl)piperazine-1-carboxylic acid5-cyano-1-(2,4-dimethoxy-phenylsulphonyl)-3-(2-methoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-ylester (according to IUPAC nomenclature:5-cyano-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-methoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl-4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate).

WO 06/005609 describes the 2-ethoxyphenyl urea compoundsN-[5-cyano-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-ethoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(1-methylpiperidin-4-yl)piperazine-1-carboxamide(as Example 119) andN-[5-cyano-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-ethoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(4-methylpiperazin-1-yl)piperidine-1-carboxamide(as Example 128).

In addition to the binding affinity to the vasopressin V1b receptor,further properties may be advantageous in the treatment and/orprophylaxis of vasopressin-dependent disorders, such as, for example:

1.) a selectivity for the vasopressin V1b receptor over the vasopressinV1a receptor, i.e. the quotient of the binding affinity to the V1areceptor (Ki(V1a) (determined in the unit “nanomolar (nM)”) and thebinding affinity to the V1b receptor (Ki(V1b)) (determined in the unit“nanomolar (nM)”). The greater the quotient Ki(V1a)/Ki(V1b), the greaterthe V1b selectivity;2.) a selectivity for the vasopressin V1b receptor over the vasopressinV2 receptor, i.e. the quotient of the binding affinity to the V2receptor (Ki(V2) (determined in the unit “nanomolar (nM)”) and thebinding affinity to the V1b receptor (Ki(V1b)) (determined in the unit“nanomolar (nM)”). The greater the quotient Ki(V2)/Ki(V1b), the greaterthe V1b selectivity;3.) a selectivity for the vasopressin V1b receptor over the oxytocin OTreceptor, i.e. the quotient of the binding affinity to the OT receptor(Ki(OT) (determined in the unit “nanomolar (nM)”) and the bindingaffinity to the V1b receptor (Ki(V1b)) (determined in the unit“nanomolar (nM)”). The greater the quotient Ki(OT)/Ki(V1b), the greaterthe V1b selectivity;4.) the metabolic stability, determined, for example, using thehalf-life determined in vitro in liver microsomes of various species(for example rat or human);5.) only minor, if any, inhibition of cytochrom P450 (CYP)enzymes:cytochrom P450 (CYP) is the name for a superfamily of haemproteins having enzymatic activity (oxidases). They are also ofparticular importance for the degradation (metabolism) of foreignsubstances, such as pharmaceutics or xenobiotics, in mammalianorganisms. The most important representatives of the types and subtypesof CYP in the human organism are: CYP 1A2, CYP 2C9, CYP 2D6 and CYP 3A4.When CYP 3A4 inhibitors (for example grapefruit juice, cimetidine,erythromycin) and medicaments which are degraded via this enzyme systemand which thus compete for the same binding site at the enzyme areadministered simultaneously, their degradation may be slowed down, andactions and side-effects of the medicament administered may be enhancedin an unwanted manner;6.) suitable solubility in water (in mg/ml);7.) suitable pharmacokinetics (temporal profile of the concentration ofthe compound according to the invention in the plasma or in tissues, forexample brain). Pharmacokinetics may be described by the followingparameters: half-life, distribution volume, plasma clearance, AUC (“areaunder the curve”, area under the concentration-time curve), oralbioavailability, the brain/plasma ratio;8.) a certain proportion of the active substance is present attached toplasma proteins (drug/plasma protein binding (PPB) value);9.) no or only minor blockage of the hERG channel: compounds which blockthe hERG channel may prolong the QT interval, thus leading to seriousirregularities of pulse (for example “torsade de pointes”). Using adisplacement assay described in the literature with radioactivelylabelled dofetilide (G. J. Diaz et al., Journal of Pharmacological andToxicological Methods, 50 (2004), 187-199), it is possible to determinethe potential of compounds of blocking the hERG channels. The lower theIC50 in this “dofetilide assay”, the more likely a potent hERG blockage.In addition, the blockage of the hERG channel may be measured byelectrophysical experiments using cells transfected with the hERGchannel, by “whole-cell patch clamping” (G. J. Diaz et al., Journal ofPharmacological and Toxicological Methods, 50 (2004), 187-199).

It is an object of the present invention to provide a compound with highand selective activity, preferably in particular for the vasopressin V1breceptor, for the treatment or prophylaxis of variousvasopressin-dependent diseases. In addition, the substance according tothe invention should have one or more of the advantages 1.) to 9.)mentioned above, in particular a suitable selectivity for the V1breceptor over the V1a receptor.

This object is achieved by compounds of the general formula (I)

in which

-   -   R1 is ethoxy;    -   R2 is hydrogen;    -   R3 is cyano;    -   R4 is hydrogen;    -   R5 is hydrogen, methoxy or ethoxy;    -   R6 is hydrogen or methoxy;    -   R7 is hydrogen, methyl, ethyl, n-propyl or isopropyl;    -   X1 is —NH—;    -   X2 is N or CH;    -   X3 is N or CH;        where X2 and X3 are not simultaneously N (that is to say are a        nitrogen atom); and by the pharmaceutically acceptable salts,        tautomeric forms, and prodrugs thereof.

Accordingly, the present invention relates to compounds of the generalformula (I) (also “compounds (I)” below), including the tautomeric formsthereof, and the pharmaceutically acceptable salts of the compounds (I)and the prodrugs of the compounds (I).

A preferred subject-matter of the invention are compounds of the generalformula (I) in which

R1 is ethoxy;R2 is hydrogen;R3 is cyano;R4 is hydrogen;R5 is hydrogen or methoxy, in particular methoxy;R6 is hydrogen or methoxy, in particular methoxy;R7 is hydrogen, methyl, ethyl, n-propyl or isopropyl;

X1 is —NH—; X2 is N or CH; X3 is N or CH;

where X2 and X3 are not simultaneously a nitrogen atom;and the pharmaceutically acceptable salts, tautomeric forms, andprodrugs thereof.

A particularly preferred subject-matter of the invention are compoundsof the general formula (I) in which

R1 is ethoxy;R2 is hydrogen;R3 is cyano;R4 is hydrogen;R5 is hydrogen or methoxy, in particular methoxy;R6 is hydrogen or methoxy, in particular methoxy, in particular methylor ethyl;R7 is hydrogen, methyl or ethyl;

X1 is —NH—; X2 is N; X3 is CH;

and the pharmaceutically acceptable salts, tautomeric forms, andprodrugs thereof.

A further particularly preferred subject-matter of the invention arecompounds of the general formula (I) in which

R1 is ethoxy;R2 is hydrogen;R3 is cyano;R4 is hydrogen;R5 is hydrogen or methoxy, in particular methoxy;R6 is hydrogen or methoxy, in particular methoxy;R7 is hydrogen, methyl or ethyl, in particular methyl or ethyl;

X1 is —NH—; X2 is CH; X3 is N;

and the pharmaceutically acceptable salts, tautomeric forms, andprodrugs thereof.

A further particularly preferred subject-matter of the invention arecompounds of the general formula (I) in which

R1 is ethoxy;R2 is hydrogen;R3 is cyano;R4 is hydrogen;R5 is hydrogen or methoxy, in particular methoxy;R6 is hydrogen or methoxy, in particular methoxy;R7 is hydrogen, methyl or ethyl, in particular methyl or ethyl;

X1 is —NH—; X2 is CH; X3 is CH;

and the pharmaceutically acceptable salts, tautomeric forms, andprodrugs thereof.

A further particularly preferred subject-matter of the invention arecompounds of the general formula (I) in which

R1 is ethoxy;R2 is hydrogen;R3 is cyano;R4 is hydrogen;R5 is methoxy;R6 is methoxy;R7 is methyl or ethyl;

X1 is —NH—; X2 is CH and X3 is N; or X2 is N and X3 is CH;

and the pharmaceutically acceptable salts, tautomeric forms, andprodrugs thereof.

Examples of preferred embodiments of the present invention are compoundsaccording to the general formula (I), and the pharmaceuticallyacceptable salts, tautomeric forms, and prodrugs thereof, in which

R1 is ethoxy,R2 is hydrogen,R3 is cyano,R4 is hydrogen,

X1 is NH,

and in which the radicals X2, X3, R5, R6 and R7 have in each case themeanings listed in one of the rows of Table 1 below.

TABLE 1 Example No. X2 X3 R5 R6 R7 1 N CH methoxy methoxy methyl 2 N CHmethoxy H methyl 3 N CH ethoxy H methyl 4 N CH H H methyl 5 N CH Hmethoxy methyl 6 N CH ethoxy methoxy methyl 7 N CH methoxy methoxy ethyl8 N CH methoxy H ethyl 9 N CH ethoxy H ethyl 10 N CH H H ethyl 11 N CH Hmethoxy ethyl 12 N CH ethoxy methoxy ethyl 13 N CH methoxy methoxyn-propyl 14 N CH methoxy H n-propyl 15 N CH ethoxy H n-propyl 16 N CH HH n-propyl 17 N CH H methoxy n-propyl 18 N CH ethoxy methoxy n-propyl 19N CH methoxy methoxy isopropyl 20 N CH methoxy H isopropyl 21 N CHethoxy H isopropyl 22 N CH H H isopropyl 23 N CH H methoxy isopropyl 24N CH ethoxy methoxy isopropyl 25 N CH methoxy methoxy H 26 N CH methoxyH H 27 N CH ethoxy H H 28 N CH H H H 29 N CH H methoxy H 30 N CH ethoxymethoxy H 31 CH N methoxy methoxy methyl 32 CH N methoxy H methyl 33 CHN ethoxy H methyl 34 CH N H H methyl 35 CH N H methoxy methyl 36 CH Nethoxy methoxy methyl 37 CH N methoxy methoxy ethyl 38 CH N methoxy Hethyl 39 CH N ethoxy H ethyl 40 CH N H H ethyl 41 CH N H methoxy ethyl42 CH N ethoxy methoxy ethyl 43 CH N methoxy methoxy n-propyl 44 CH Nmethoxy H n-propyl 45 CH N ethoxy H n-propyl 46 CH N H H n-propyl 47 CHN H methoxy n-propyl 48 CH N ethoxy methoxy n-propyl 49 CH N methoxymethoxy isopropyl 50 CH N methoxy H isopropyl 51 CH N ethoxy H isopropyl52 CH N H H isopropyl 53 CH N H methoxy isopropyl 54 CH N ethoxy methoxyisopropyl 55 CH N methoxy methoxy H 56 CH N methoxy H H 57 CH N ethoxy HH 58 CH N H H H 59 CH N H methoxy H 60 CH N ethoxy methoxy H 61 CH CHmethoxy methoxy methyl 62 CH CH methoxy H methyl 63 CH CH ethoxy Hmethyl 64 CH CH H H methyl 65 CH CH H methoxy methyl 66 CH CH ethoxymethoxy methyl 67 CH CH methoxy methoxy ethyl 68 CH CH methoxy H ethyl69 CH CH ethoxy H ethyl 70 CH CH H H ethyl 71 CH CH H methoxy ethyl 72CH CH ethoxy methoxy ethyl 73 CH CH methoxy methoxy n-propyl 74 CH CHmethoxy H n-propyl 75 CH CH ethoxy H n-propyl 76 CH CH H H n-propyl 77CH CH H methoxy n-propyl 78 CH CH ethoxy methoxy n-propyl 79 CH CHmethoxy methoxy isopropyl 80 CH CH methoxy H isopropyl 81 CH CH ethoxy Hisopropyl 82 CH CH H H isopropyl 83 CH CH H methoxy isopropyl 84 CH CHethoxy methoxy isopropyl 85 CH CH methoxy methoxy H 86 CH CH methoxy H H87 CH CH ethoxy H H 88 CH CH H H H 89 CH CH H methoxy H 90 CH CH ethoxymethoxy H

In particular, the present invention relates to the following compoundof the formula Ia (which corresponds to compound Example 1 of table 1)

and also the pharmaceutically acceptable salts, tautomeric forms, andprodrugs of Ia.

In particular, the present invention also relates to the compoundExample 7 of table 1 and also to the pharmaceutically acceptable salts,tautomeric forms, and prodrugs thereof.

In particular, the present invention also relates to the compoundExample 31 of table 1 and also to the pharmaceutically acceptable salts,tautomeric forms, and prodrugs thereof.

In particular, the present invention also relates to the compoundExample 37 of table 1 and also to the pharmaceutically acceptable salts,tautomeric forms, and prodrugs thereof.

The compounds (I) or (Ia) of the invention have a centre of chirality inposition 3 of the 2-oxindole ring. The compounds according to theinvention of the general formula (I) or (Ia) may therefore be present asa 1:1 mixture of enantiomers (racemate), or as a non-racemic mixture ofenantiomers in which one of the two enantiomers, i.e. either the(laevorotatory) enantiomer which turns the plane of polarization oflinear polarized light to the left ((−)-enantiomer below), or the(dextrorotatory) enantiomer which turns the plane of polarization oflinear polarized light to the right ((+)-enantiomer below), is enriched,or as essentially enantiomerically pure compounds (enantiomeric excessee >90%), i.e. as essentially enantiomerically pure (−)-enantiomer or(+)-enantiomer. Preferably, the compounds are present as essentiallyenantiomerically pure compounds. Particular preference is given tocompounds which are essentially enantiomerically pure (ee >90%).

The invention therefore provides the pure enantiomers as well as theirmixtures, for example, mixtures in which one enantiomer is present inenriched form, but also the racemates. The invention also provides thepharmaceutically acceptable salts, the tautomers and the prodrugs of thepure enantiomers of (I) or (Ia), and the enantiomer mixtures in the formof the pharmaceutically acceptable salts, the tautomers and the prodrugsof (I) or (Ia).

Preferred embodiments of the invention are compounds of the generalformula (I) or (Ia), as defined above, which are characterized in thatthey are present in optically active form and that they are in each casethe enantiomer, which rotates the plane of polarization of polarizedlight to the left, (i.e. the laevorotatory enantiomer) of the compoundof the general formula (I) in question in the form of the free base, ora pharmaceutically acceptable salt, a tautomeric form or a prodrugthereof. Below, the laevorotatory enantiomers of the compounds (I) or(Ia) are also referred to as (−)-enantiomers.

Preferred embodiments of the invention are those compounds of thegeneral formula (I) or (Ia), as defined above, which are characterizedin that they are present in optically active form, where the absoluteconfiguration of the chiral C-3 ring carbon atom of these compoundscorresponds to the absolute configuration at C-3 of the (−)-enantiomerof the compound of the formula (Ia) in the form of the free base. Thisconfiguration is also referred to below as the “preferredconfiguration”. X-Ray structure analyses have shown that the(−)-enantiomer of the compounds of the formula (Ia) has S configurationwith respect to the centre of asymmetry at the carbon atom of position 3of the oxindole ring.

According to the invention, preference is given to compounds of thegeneral formula (I) or (Ia), tautomers thereof, pharmaceuticallyacceptable salts thereof and prodrugs thereof, as defined above, inwhich the corresponding (−)-enantiomer is present in an optical purity(enantiomeric excess, ee) of greater than 50%.

According to the invention, preference is given to compounds of thegeneral formula (I) or (Ia), tautomers thereof, pharmaceuticallyacceptable salts thereof and prodrugs thereof, as defined above, inwhich the enantiomer having the preferred absolute configuration at theC-3 ring carbon atom is present in an optical purity (enantiomericexcess, ee) of greater than 50%.

According to the invention, preference is given to compounds of thegeneral formula (I) or (Ia), tautomers thereof, pharmaceuticallyacceptable salts thereof and prodrugs thereof, as defined above, inwhich the corresponding (−)-enantiomer is present in an optical purity(enantiomeric excess, ee) of greater than 90%.

According to the invention, preference is given to compounds of thegeneral formula (I) or (Ia), tautomers thereof, pharmaceuticallyacceptable salts thereof and prodrugs thereof, as defined above, inwhich the enantiomer having the preferred absolute configuration at theC-3 ring carbon atom is present in an optical purity (enantiomericexcess, ee) of greater than 90%.

Likewise preferred embodiments of the invention are compounds of thegeneral formula (I) or (Ia) as defined above, which are characterized inthat they are present in optically inactive form, that is to say in theform of the racemate, or in the form of a pharmaceutically acceptablesalt, a tautomeric form or a prodrug of the racemate.

A further subject-matter of the present invention relates to medicamentscomprising at least one compound of the general formula (I) or (Ia)and/or a pharmaceutically acceptable salt or a prodrug thereof asdefined above.

A further subject-matter of the present invention relates to compoundsof the general formula (I) or (Ia) and/or a pharmaceutically acceptablesalt or a prodrug thereof as defined above for use as a medicament.

A further subject-matter of the present invention relates to thecompounds of the formula (I) or (Ia) and/or a pharmaceuticallyacceptable salt or a prodrug thereof as defined above for use in therapyor prophylaxis of a disease, in particular a vasopressin-dependentdisease or a disease mentioned herein.

A further subject-matter of the present invention relates to the use ofat least one compound of the general formula (I) or (Ia) and/or apharmaceutically acceptable salt or a prodrug thereof as defined abovefor the treatment and/or prophylaxis of at least onevasopressin-dependent disease and/or for the manufacture of a medicamentfor the treatment and/or a prophylaxis of at least onevasopressin-dependent disease. Vasopressin-dependent diseases are thosein which the progression of the disease depends at least in part onvasopressin, i.e. diseases where the vasopressin level, which maycontribute directly or indirectly to the disease picture, is elevated.

The present invention also relates to the use of the compounds (I) or(Ia) according to the invention and/or a pharmaceutically acceptablesalt or a prodrug thereof for the treatment and/or prophylaxis ofdiseases in which the progression of the disease depends at least inpart on vasopressin, i.e. diseases where the vasopressin level, whichmay contribute directly or indirectly to the disease picture, iselevated. The present invention also relates to the use of the compounds(I) or (Ia) according to the invention and/or a pharmaceuticallyacceptable salt or a prodrug thereof for preparing a medicament for thetreatment and/or prophylaxis of such a disease.

The present invention relates in particular to the use of at least onecompound of the general formula (I) or (Ia) and/or a pharmaceuticallyacceptable salt or a prodrug thereof as defined above for the treatmentand/or prophylaxis of at least one disorder selected from the groupconsisting of diabetes, in particular diabetes insipidus, insulinresistance, nocturnal enuresis, incontinence, diseases in which bloodcoagulation disorders occur, and/or for delaying micturition and the usethereof for the manufacture of a medicament for the treatment and/orprophylaxis of at least one of said diseases.

The present invention relates in particular to the use of at least onecompound of the general formula (I) or (Ia) and/or a pharmaceuticallyacceptable salt or a prodrug thereof as defined above for the treatmentand/or prophylaxis of at least one disorder selected from the groupconsisting of hypertension, pulmonary hypertension, heart failure,myocardial infarction, coronary spasm, unstable angina, PTCA(percutaneous transluminal coronary angioplasty), ischemias of theheart, disorders of the renal system, edemas, renal vasospasm, necrosisof the renal cortex, hyponatremia, hypokalemia, Schwartz-Barttersyndrome, disorders of the gastrointestinal tract, gastritic vasospasm,hepatocirrhosis, gastric and intestinal ulcer, emesis, emesis occurringduring chemotherapy, and travel sickness, and the use thereof for themanufacture of a medicament for the treatment and/or prophylaxis of atleast one of said diseases.

The compounds (I) or (Ia) of the invention, their salts, their tautomersand their prodrugs can also be used for the treatment of variousvasopressin-dependent complaints which exhibit central nervous causes oralterations in the HPA axis (hypothalamic pituitary adrenal axis), forexample for affective disorders such as depressive disorders and bipolardisorders. These include for example dythymic disorders, phobias,post-traumatic stress disorders, general anxiety disorders, panicdisorders, seasonal depressions and sleep disorders.

The compounds (I) or (Ia) of the invention, their salts, their tautomersand their prodrugs can likewise be employed for treatment in cases ofanxiety disorders and stress-dependent anxiety disorders such as, forexample, generalized anxiety disorders, phobias, post-traumatic anxietydisorders, panic anxiety disorders, obsessive-compulsive anxietydisorders, acute stress-dependent anxiety disorders and social phobia.The compounds of the invention can further be employed also for thetreatment of memory impairments, Alzheimer's disease, psychoses,psychotic disorders, sleep disorders and/or Cushing's syndrome, and allstress-dependent diseases.

A further subject-matter of the invention relates to the use of at leastone compound of the general formula (I) or (Ia) and/or apharmaceutically acceptable salt or a prodrug thereof as defined abovefor the treatment of affective disorders and/or for the manufacture of amedicament for the treatment of affective disorders.

A further subject-matter of the invention relates to the use of at leastone compound of the general formula (I) or (Ia) and/or apharmaceutically acceptable salt or a prodrug thereof as defined abovefor the treatment of anxiety disorders and/or stress-dependent anxietydisorders and/or for the manufacture of a medicament for the treatmentof anxiety disorders and/or stress-dependent anxiety disorders.

A further subject-matter of the invention relates to the use of at leastone compound of the general formula (I) or (Ia) and/or apharmaceutically acceptable salt or a prodrug thereof as defined abovefor the treatment of memory impairments and/or Alzheimer's diseaseand/or for the manufacture of a medicament for the treatment of memoryimpairments and/or Alzheimer's disease.

A further subject-matter of the invention relates to the use of at leastone compound of the general formula (I) or (Ia) and/or apharmaceutically acceptable salt or a prodrug thereof as defined abovefor the treatment of psychoses and/or psychotic disorders and/or for themanufacture of a medicament for the treatment of psychoses and/orpsychotic disorders.

A further subject-matter of the invention relates to the use of at leastone compound of the general formula (I) or (Ia) and/or apharmaceutically acceptable salt or a prodrug thereof as defined abovefor the treatment of Cushing's syndrome or other stress-dependentdiseases and/or for the manufacture of a medicament for the treatment ofCushing's syndrome or other stress-dependent diseases.

A further subject-matter of the invention relates to the use of at leastone compound of the general formula (I) or (Ia) and/or apharmaceutically acceptable salt or a prodrug thereof as defined abovefor the treatment of sleep disorders and/or for the manufacture of amedicament for the treatment of sleep disorders.

A further subject-matter of the invention relates to the use of at leastone compound of the general formula (I) or (Ia) and/or apharmaceutically acceptable salt or a prodrug thereof as defined abovefor the treatment of depressive disorders and/or for the manufacture ofa medicament for the treatment of depressive disorders.

A further subject-matter of the invention relates to the use of at leastone compound of the general formula (I) or (Ia) and/or apharmaceutically acceptable salt or a prodrug thereof as defined abovefor the treatment of childhood onset mood disorders and/or for themanufacture of a medicament for the treatment of childhood onset mooddisorders. The term “childhood onset mood disorders” is understood tomean mood disorders and depressions which begin as early as childhood.

A further subject-matter of the invention relates to the use of at leastone compound of the general formula (I) or (Ia) and/or apharmaceutically acceptable salt or a prodrug thereof as defined abovefor the treatment of vasomotor symptoms and/or thermoregulatorydysfunctions, such as, for example, the “hot flush” symptom.

A further subject-matter of the invention relates to the use of at leastone compound of the general formula (I) or (Ia) and/or apharmaceutically acceptable salt or a prodrug thereof as defined abovefor the treatment and/or prophylaxis of drug dependencies, medicamentdependencies and/or dependencies mediated by other factors, for thetreatment and/or prophylaxis of stress caused by the withdrawal of oneor more factors mediating the dependency and/or for the treatment and/orprophylaxis of stress-induced relapses into the drug dependencies,medicament dependencies and/or dependencies mediated by other factors.

A further subject-matter of the invention relates to the use of at leastone compound of the general formula (I) or (Ia) and/or apharmaceutically acceptable salt or a prodrug thereof as defined abovefor the treatment and/or prophylaxis of schizophrenia and/or psychosis.

A further subject-matter of the invention relates to a method for thetreatment and/or prophylaxis of at least one disorder selected from thegroup consisting of diabetes, in particular diabetes insipidus, insulinresistance, nocturnal enuresis, incontinence, diseases in which bloodcoagulation disorders occur, and for delaying micturition in a patient,characterized in that an effective amount of at least one compound ofthe general formula (I) or (Ia) and/or a pharmaceutically acceptablesalt or a prodrug thereof is administered to the patient.

A further subject-matter of the invention relates to a method for thetreatment and/or prophylaxis of at least one disorder selected from thegroup consisting of hypertension, pulmonary hypertension, heart failure,myocardial infarction, coronary spasm, unstable angina, PTCA(percutaneous transluminal coronary angioplasty), ischemias of theheart, disorders of the renal system, edemas, renal vasospasm, necrosisof the renal cortex, hyponatremia, hypokalemia, Schwartz-Barttersyndrome, disorders of the gastrointestinal tract, gastritic vasospasm,hepatocirrhosis, gastric and intestinal ulcer, emesis, emesis occurringduring chemotherapy, and travel sickness in a patient, characterized inthat an effective amount of at least one compound of the general formula(I) or (Ia) and/or a pharmaceutically acceptable salt or a prodrugthereof is administered to the patient.

A further subject-matter of the invention relates to a method for thetreatment and/or prophylaxis of affective disorders in a patient,characterized in that an effective amount of at least one compound ofthe general formula (I) or (Ia) and/or a pharmaceutically acceptablesalt or a prodrug thereof is administered to the patient.

A further subject-matter of the invention relates to a method for thetreatment of anxiety disorders and/or stress-dependent anxiety disordersin a patient, characterized in that an effective amount of at least onecompound of the general formula (I) or (Ia) and/or a pharmaceuticallyacceptable salt or a prodrug thereof is administered to the patient.

A further subject-matter of the invention relates to a method for thetreatment of memory impairments and/or Alzheimer's disease in a patient,characterized in that an effective amount of at least one compound ofthe general formula (I) or (Ia) and/or a pharmaceutically acceptablesalt or a prodrug thereof is administered to the patient.

A further subject-matter of the invention relates to a method for thetreatment of psychoses and/or psychotic disorders in a patient,characterized in that an effective amount of at least one compound ofthe general formula (I) or (Ia) and/or a pharmaceutically acceptablesalt or a prodrug thereof is administered to the patient.

A further subject-matter of the invention relates to a method for thetreatment of Cushing's syndrome in a patient, characterized in that aneffective amount of at least one compound of the general formula (I) or(Ia) and/or a pharmaceutically acceptable salt or a prodrug thereof isadministered to the patient.

A further subject-matter of the invention relates to a method for thetreatment of sleep disorders in a patient, characterized in that aneffective amount of at least one compound of the general formula (I) or(Ia) and/or a pharmaceutically acceptable salt or a prodrug thereof isadministered to the patient.

A further subject-matter of the invention relates to a method for thetreatment of depressive disorders in a patient, characterized in that aneffective amount of at least one compound of the general formula (I) or(Ia) and/or a pharmaceutically acceptable salt or a prodrug thereof isadministered to the patient.

A further subject-matter of the invention relates to a method for thetreatment and/or prophylaxis of vasomotor symptoms and/orthermoregulatory dysfunctions, such as, for example, the “hot flush”symptom, in a patient, characterized in that an effective amount of atleast one compound of the general formula (I) or (Ia) and/or apharmaceutically acceptable salt or a prodrug thereof is administered tothe patient.

A further subject-matter of the invention relates to a method for thetreatment and/or prophylaxis of drug dependencies, medicamentdependencies and/or dependencies mediated by other factors, for thetreatment and/or prophylaxis of stress caused by the withdrawal of oneor more factors mediating the dependency and/or for the treatment and/orprophylaxis of stress-induced relapses in the drug dependencies,medicament dependencies and/or dependencies mediated by other factors,in a patient, characterized in that an effective amount of at least onecompound of the general formula (I) or (Ia) and/or pharmaceuticallyacceptable salt or a prodrug thereof is administered to the patient.

A further subject-matter of the invention relates to a method for thetreatment and/or prophylaxis of schizophrenia and/or psychosis in apatient, characterized in that an effective amount of at least onecompound of the general formula (I) or (Ia) and/or a pharmaceuticallyacceptable salt or a prodrug thereof is administered to the patient.

A further subject-matter of the invention relates to a method as definedabove, which is characterized in that the patient is a mammal,preferably a human or a nonhuman mammal or a nonhuman transgenic mammal.

The compounds of the general formula (I) or (Ia), their pharmaceuticallyacceptable salts and prodrugs as defined above can be prepared by askilled worker with knowledge of the technical teaching of the inventionin implementation and/or in analogous implementation of process stepsknown per se.

A further preferred embodiment relates to compounds of the generalformula (I) or (Ia), their tautomers, their prodrugs thereof and theirpharmaceutically acceptable salts as described above, which arecharacterized in that they are selective for the vasopressin receptorsubtype V1b over at least one of the closely relatedvasopressin/oxytocin receptor subtypes (for example vasopressin V1a,vasopressin V2 and/or oxytocin).

A further preferred embodiment relates to compounds of the generalformula (I) or (Ia), their tautomers, their prodrugs thereof and theirpharmaceutically acceptable salts as described above, which arecharacterized in that they have improved metabolic stability.

The metabolic stability of a compound can be determined, for example, byincubating a solution of this compound with liver microsomes fromparticular species (for example rat, dog or human) and determining thehalf-life of the compound under these conditions (RS Obach, Curr OpinDrug Discov Devel. 2001, 4, 36-44). It is possible to conclude from anobserved larger half-life that the metabolic stability of the compoundis improved. The stability in the presence of human liver microsomes isof particular interest since it makes it possible to predict themetabolic degradation of the compound in the human liver. Compounds withincreased metabolic stability (determined in the liver microsome test)are therefore probably also degraded more slowly in the liver. Theslower metabolic degradation in the liver can lead to higher and/orlonger-lasting concentrations (effective levels) of the compound in thebody, so that the elimination half-life of the compounds according tothe invention is increased. Increased and/or longer-lasting effectivelevels may lead to a better efficacy of the compound in the treatment orprophylaxis of various vasopressin-dependent diseases. An improvedmetabolic stability may additionally lead to an increasedbioavailability after oral administration, because the compound issubjected, after being absorbed in the intestine, to less metabolicdegradation in the liver (so-called first pass effect). An increasedoral bioavailability may, because the concentration (effective level) ofthe compound is increased, lead to a better efficacy of the compoundafter oral administration.

A further preferred embodiment relates to compounds of the generalformula (I) as described above, characterized in that, in patients orrelevant animal models allowing prognostic statements on therapeuticapplication, they have improved pharmacological activity compared to theoxindole compounds known from the prior art.

Each of the stated preferred definitions of a variable may be combinedwith any definitions of the remaining variables.

The invention relates in particular to compounds of the general formula(I) which are selected from the group consisting of the examples, listedbelow, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36,37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54,55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72,73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89 and90, and also to their tautomeric forms, their prodrugs and in particulartheir physiologically acceptable salts, and their non-salt forms such ashydrates and/or solvates. Particular preference is given to providingthe abovementioned compounds in the form of the free base or in the formof acid addition salts.

The invention in particular also relates to the (−)-enantiomers of theExamples 1 to 90 in accordance with the general formula (I) selectedfrom the compounds of the examples, listed below, 1B, 2B, 3B, 4B, 5B,6B, 7B, 8B, 9B, 10B, 11B, 12B, 13B, 14B, 15B, 16B, 17B, 18B, 19B, 20B,21B, 22B, 23B, 24B, 25B, 26B, 27B, 28B, 29B, 30B, 31B, 32B, 33B, 34B,35B, 36B, 37B, 38B, 39B, 40B, 41B, 42B, 43B, 44B, 45B, 46B, 47B, 48B,49B, 50B, 51B, 52B, 53B, 54B, 55B, 56B, 57B, 58B, 59B, 60B, 61B, 62B,63B, 64B, 65B, 66B, 67B, 68B, 69B, 70B, 71B, 72B, 73B, 74B, 75B, 76B,77B, 78B, 79B, 80B, 81B, 82B, 83B, 84B, 85B, 86B, 87B, 88B, 89B and 90B,and also to tautomeric forms, prodrugs and in particular physiologicallyacceptable salts, and non-salt forms such as hydrates and/or solvates ofcompounds of the formula (I). Particular preference is given toproviding the abovementioned compounds in the form of the free base orin the form of acid addition salts.

The term “prodrugs” is to be understood as meaning those compounds whichare metabolized in vivo to the compounds according to the invention.Typical examples of prodrugs are described in C. G. Wermeth (Ed.): ThePractice of Medicinal Chemistry, Academic Press, San Diego, 1996, pages671-715. They include, for example, phosphates, carbamates or aminoacids, esters and others. In the present invention suitable prodrugs ofthe compounds of the formula are compounds of the formula I, where thenitrogen atom that carries R7 is part of an amide/peptide group, i.e.the nitrogen carries a acyl group such as C1-C4-alkylcarbonyl e.g.acetyl, propionyl, n-butyryl (n-propylcarbonyl), isobutyryl,n-butylcarbonyl oder tert-butylcarbonyl (pivaloyl), benzoyl, CO boundradical derived from an amino acid such as a CO bound radical derivedfrom glycine, alanine, serine, phenylalanine etc. Suitable prodrugs olsoinclude alkylcarbonyloxyalkylcarbamate, wherein the radical R7 informula I is a moiety of the formula —C(═O)—O—CHR^(a)—O—C(═O)—R^(b)wherein R^(a) and R^(b) are independently of each other are selectedfrom C₁-C₄-alkyl. Such carbamates have been generally described by J.Alexander, R. Cargill, S. R. Michelson, H. Schwam, J. Medicinal Chem.1988, 31(2), 318-322. These groups are cleaved under metabolicconditions to yield a compound of the formula I, wherein R7 is hydrogen.

The invention furthermore relates to the pharmaceutically acceptablesalts of compounds of the formula I, which are also referred to asphysiologically acceptable salts. The salts are generally obtainable byreacting the free base of the compounds (I) according to the inventionwith a suitable acid. Suitable acids are listed, for example, in“Fortschritte der Arzneimittelforschung” [Advances in Drug Research],1966, Birkhäuser Verlag, Vol. 10, pp. 224-285. They include, forexample, hydrochloric acid, citric acid, tartaric acid, lactic acid,phosphoric acid, methanesulphonic acid, acetic acid, formic acid, maleicacid and fumaric acid.

The compounds of the invention are effective after administration byvarious routes. The administration can, for example, be carried outintravenously, intramuscularly, subcutaneously, topically,intratracheally, intranasally, transdermally, vaginally, rectally,sublingually, buccally or orally and is frequently carried outintravenously, intramuscularly or in particular orally.

The present invention also relates to pharmaceutical compositions whichcomprise a compound (I) of the invention, and/or a tautomer, and/or apharmaceutically acceptable salt and/or a prodrug thereof and suitablepharmaceutical carriers (drug carriers). The amount of compound I in thepharmaceutical composition may depend on the formulation type of thecomposition and may be e.g. in the range from 0.0001 mg/g to 1 g/g inparticular from 0.001 mg/g to 0.5 g/g of the composition.

These drug carriers are chosen according to the pharmaceutical form andthe desired mode of administration.

The compounds of the invention of the general formula (I) or, whereappropriate, suitable salts of these compounds can be used tomanufacture pharmaceutical compositions for oral, sublingual, buccal,subcutaneous, intramuscular, intravenous, topical, intratracheal,intranasal, transdermal, vaginal or rectal administration and beadministered to animals or humans in unit dose forms mixed withconventional pharmaceutical carriers for the prophylaxis or treatment ofthe above disorders or diseases.

Suitable uniform administration forms (unit dose forms) comprise formsfor oral administration, such as tablets, gelatin capsules, powders,granules, solutions or suspensions for oral intake, forms forsublingual, buccal, intratracheal or intranasal administration,aerosols, implants, forms of subcutaneous, intramuscular or intravenousadministration and forms of rectal administration.

The compounds of the invention can be used in creams, ointments orlotions for topical administration.

In order to achieve the desired prophylactic or therapeutic effect, thedose of the active compound can vary between 0.01 and 50 mg per kg ofbody weight and per day.

Each unit dose may comprise from 0.05 to 5000 mg, preferably 1 to 1000mg, of the active compound in combination with a pharmaceutical carrier.This unit dose can be administered 1 to 5 times a day so that a dailydose of from 0.5 to 25 000 mg, preferably 1 to 5000 mg, is administered.

If a solid composition in the form of tablets is prepared, the activecompound is mixed with a pharmaceutical carrier such as gelatin, starch,lactose, magnesium stearate, talc, silicon dioxide or the like.

The tablets can be coated with sucrose, a cellulose derivative oranother suitable substance or be treated otherwise in order to display aprolonged or delayed activity and in order to release a predeterminedamount of the active compound continuously.

A preparation in the form of gelatin capsules is obtained by mixing theactive compound with an extender and taking up the resulting mixture insoft or hard gelatin capsules.

A preparation in the form of a syrup or elixir or for administration inthe form of drops may comprise active compounds together with asweetener which is preferably calorie-free, methylparaben orpropylparaben as antiseptics, a flavouring and a suitable colouring.

The water-dispersible powders or granules may comprise the activecompounds mixed with dispersants, wetting agents or suspending agents,such as polyvinylpyrrolidones, and sweeteners or taste improvers.

Rectal or vaginal administration is achieved by the use of suppositorieswhich are prepared with binders which melt at the rectal temperature,for example cocoa butter or polyethylene glycols. Parenteraladministration is effected by using aqueous suspensions, isotonic saltsolutions or sterile and injectable solutions which comprisepharmacologically suitable dispersants and/or wetting agents, forexample propylene glycol or polyethylene glycol.

The active compound can also be formulated as microcapsules orcentrosomes, if suitable with one or more carriers or additives.

In addition to the compounds of the general formula (I), or theirpharmaceutically acceptable salts or prodrugs, the compositions of theinvention may comprise further active compounds which may be beneficialfor the treatment of the impairments or disorders indicated above.

The present invention therefore further relates to pharmaceuticalcompositions which comprise a plurality of active compounds, where atleast one of these is a compound (I) according to the invention, atautomer, a salt or a prodrug thereof.

Preparation of the Compounds of the Invention

Examples of synthetic routes for preparing the oxindole derivatives ofthe invention are described below.

The preparation of the oxindoles according to the invention can becarried out by different routes as illustrated in synthesis schemes 1and 2. In these synthesis schemes, the variables have the same meaningsas in the general formula (I).

The 3-hydroxy-1,3-dihydroindol-2-ones IV can be obtained by addingmetallated heterocycles III to the 3-keto group of the isatins II. Themetallated heterocycles, such as, for example, the correspondingGrignard (Mg) or organyllithium compound, can be obtained in a customarymanner from halogen or hydrocarbon compounds. Exemplary procedures canbe found in Houben-Weyl, Methoden der Organischen Chemie [Methods oforganic chemistry], Vol. 13, 1-2, Chap. Mg and Li compounds. The isatinsII are either commercially available or were prepared in analogy tomethods described in the literature (Advances in Heterocyclic Chemistry,A. R. Katritzky and A. J. Boulton, Academic Press, New York, 1975, 18,2-58; J. Brazil. Chem. Soc. 12, 273-324, 2001).

Using KCN or Zn(CN)₂ with Pd(0) catalysis in solvents such asdimethylformamide or tetrahydrofuran, if appropriate also with additionof bases such as K₂CO₃ or other carbonates and amines, it is possible toconvert, at elevated temperature, the 3-hydroxyoxindoles IV which, inthe 6-membered aromatic ring contain, for example as radical R³ or R⁴,an iodine substituent, into the analogous cyano-containing3-hydroxyoxindoles IV. Suitable for use as Pd(0) salts are, for example,transition metal complexes prepared in situ from PdCl₂ or PdOAc₂ byaddition of phosphines, such as tris(orthotolyl)phosphine. It is alsopossible to use commercial palladium complexes, such as, for example,the catalyst tetrakis(triphenylphosphine)palladium(0) and/or addedphosphine ligands.

The 3-hydroxyoxindoles IV can be converted into the compounds V whichcarry a leaving group LG′ in position 3, where the leaving group LG′ maybe a customary leaving group, such as, for example, halide, mesylate ortosylate. The intermediate V where, for example, LG′=chlorine, can beprepared by treating the alcohol IV with thionyl chloride in thepresence of a base, such as, for example, pyridine. Alternatively, it ispossible to obtain alcohols IV by conversion into the mesylate usingmethanesulphonyl chloride in the presence of a base, such as, forexample, triethylamine. The compounds V are subsequently reacted withamines, such as, for example, ammonia, which gives the analogous aminesVI after the substitution reactions. Compounds such as VI can then,after deprotonation with a strong base, such as, for example, potassiumtert-butoxide or sodium hydride, in DMF, be converted into the productVIII by treatment with sulphonyl chlorides VII. The sulphonyl chloridesVII used are either commercially available or can be prepared in amanner analogous to known processes (see, for example, J. Med. Chem. 40,1149 (1997)).

The compounds VIII are converted into compounds IX by reaction withreagents for derivatizing amino groups, such as, for examplechloroformates, isocyanates or carbamoyl chlorides, generally usingcustomary methods (see J. March, Advanced Organic Chemistry, 1992, 4thedition., Wiley, New York, pages 417-421; 499; 903). For example, LG asleaving group may be OPhenyl in the compound IX, which is obtained byreacting VIII with phenyl chloroformate in the presence of a base, suchas, for example, pyridine.

The subsequent reaction with amines X, if appropriate at elevatedtemperature and with addition of auxiliary bases, such as, for example,triethylamine or diisopropylethylamine, gives the compounds according tothe invention of the general formula (I). The amines X are eithercommercially available or can be prepared by methods known from theliterature.

A further alternative of preparing the amine X is the reaction of amineswith aldehydes or ketones in the presence of reducing agents, such as,for example, sodium cyanoborohydride or sodium acetoxyborohydride, inthe sense of a reductive amination (J. March, Advanced OrganicChemistry, 1992, 4th edition., Wiley, New York, pages 411; 898).

As described in synthesis scheme 2, the order of the synthesis steps forpreparing the compounds I according to the invention may be rearranged,analogously to synthesis scheme 1 above. Thus, initially, the aminogroup in the compound VI is derivatized using, for example, phenylchloroformate, giving the compounds XIa and/or XIb. With excess amine Xor else with the aid of an auxiliary base, the urea derivatives XII aregenerated which can be converted in the subsequent reaction underotherwise customary conditions by deprotonation of compounds XII using astrong base, such as, for example, sodium hydride or potassiumtert-butoxide, and subsequent treatment with sulphonyl chlorides VII inDMF into the compounds I according to the invention.

Below, the invention is illustrated in more detail using examples, theexamples not being intended to be limiting.

The compounds according to the invention can be prepared via varioussynthesis routes.

The procedures mentioned, as described accordingly in synthesis schemes1 and 2, are only described in greater detail by way of example on thebasis of the examples mentioned, without being exclusively limited tothe synthesis routes 1 or 2 or analogous procedures mentioned.

EXPERIMENTAL PART Example 1N-[5-Cyano-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(1-methylpiperidin-4-yl)piperazine-1-carboxamide1a) 3-(2-Ethoxypyridin-3-yl)-3-hydroxy-5-iodo-1,3-dihydro-2H-indol-2-one

With ice-bath cooling, 20.86 g (76.40 mmol) of 5-iodoisatin were stirredin 400 ml of anhydrous tetrahydrofuran (THF), and 3.22 g (80.50 mmol,60% w/w) of sodium hydride were added a little at a time, thetemperature being kept between 0-10° C. With ice-bath cooling, thesuspension was stirred for one hour, during which the pyridine Grignardreagent was prepared. At room temperature, 20 g (80.30 mmol) of the2-ethoxy-3-iodopyridine were dissolved in 400 ml of anhydrous THF, andover a period of 5-10 minutes 95.6 ml (1M solution in THF, 95.60 mmol)of ethylmagnesium bromide were added to this solution with cooling, at atemperature between 22 and 15° C. The solution was stirred for 20minutes, during which time the colour changed from colourless toslightly yellowish.

The solution of the pyridine Grignard reagents was then, over a periodof 5-10 minutes, added to the solution, cooled in an ice-bath, of the5-iodoisatin sodium salt, the temperature fluctuating between 5 and 18°C. After the addition of the Grignard reagent had ended, the ice-bathwas removed, and the reaction mixture was stirred at room temperaturefor another 2 hours. Excess saturated ammonium chloride solution wasadded, followed by ethyl acetate, and the mixture was stirred foranother 5 minutes. The aqueous phase was removed and extracted withethyl acetate (2×). The combined organic phases were washed with water(2×), and the solvent was removed under reduced pressure. Initially,unreacted 5-iodoisatin precipitated from the still dilute solution andwas removed, and after further concentration the product, too,crystallized out. The suspension was stored in a refrigerator at 5° C.for two hours and the slightly yellowish solid was then filtered off andwashed with a little ethyl acetate. The desired3-(2-ethoxypyridin-3-yl)-3-hydroxy-5-iodo-1,3-dihydro-2H-indol-2-one(17.1 g, 43.16 mmol, 57%) was isolated after drying at 40° C.

ESI-MS [M+H⁺]=397.05 calculated for C₁₅H₁₃IN₂O₃=396.19

1b) 5-Cyano-3-hydroxy-3-(2-ethoxypyridin-3-yl)-1,3-dihydroindol-2-one

Under an atmosphere of nitrogen, 7.1 g (17.92 mmol) of3-(2-ethoxypyridin-3-yl)-3-hydroxy-5-iodo-1,3-dihydro-2H-indol-2-onewere stirred in 100 ml of anhydrous THF at room temperature. 2.1 g(17.92 mmol) of zinc cyanide were added, followed by 0.51 g (0.45 mmol)of tetrakis(triphenylphosphine)palladium(0). The reaction mixture wastransferred directly into a preheated oil bath at a temperature of 100°C. The mixture was stirred at 100° C. (oil bath temperature), and after30 minutes, another 0.51 g (0.45 mmol) of the catalyst was added. Intotal, the mixture was stirred for 2 hours. The reaction mixture wascooled to room temperature, and an excess of water was added. Themixture was extracted with ethyl acetate (3×), and the combined organicphases were washed with water (3×). The solvent was evaporated todryness under reduced pressure, and the residue was slurried with smallvolumes of ethyl acetate. A slightly yellowish solid was removed byfiltration, washed with ethyl acetate and dried in a vacuum dryingcabinet. It was possible to isolate 3.7 g (12.44 mmol, 69.4%) of thedesired product5-cyano-3-hydroxy-3-(2-ethoxypyridin-3-yl)-1,3-dihydroindol-2-one.

ESI-MS [M+H⁺]=296.05 calculated for C₁₆H₁₃N₃O₃=295.30

1c) 3-Chloro-3-(2-ethoxypyridin-3-yl)-2-oxoindoline-5-carbonitrile

Under an atmosphere of nitrogen, 6.00 g (20.32 mmol) of the5-cyano-3-hydroxy-3-(2-ethoxypyridin-3-yl)-1,3-dihydroindol-2-one weresuspended in 60 ml of anhydrous dichloromethane (dried over molecularsieve). 2.30 ml (28.45 mmol) of pyridine were then added. The reactionmixture was cooled to a temperature of 0° C., and 2.06 ml (28.45 mmol)of neat thionyl chloride were then added dropwise (exothermic reaction).The mixture was stirred at room temperature for one hour. The formationof a yellow suspension was observed. The course of the reaction wasmonitored by thin-layer chromatography (TLC) (silica gel,dichloromethane/methanol in a ratio of 95:5). The reaction mixture wascarefully poured into ice-water. After 15 minutes of stirring, theorganic phase was removed. The aqueous phase was extracted withdichloromethane (2 x). All organic phases were combined, dried overmagnesium sulphate and filtered, and the solvent was removed underreduced pressure. The product gave 5.70 g (18.17 mmol, 89%) of3-chloro-3-(2-ethoxypyridin-3-yl)-2-oxoindoline-5-carbonitrile as anamorphous solid which was used without further purification for the nextreaction.

ESI-MS [M+H⁺]=314.1 calculated for C₁₆H₁₂ClN₃O₂=313.75

1d) 3-Amino-3-(2-ethoxypyridin-3-yl)-2-oxoindoline-5-carbonitrile

5.70 g (18.17 mmol) of3-chloro-3-(2-ethoxypyridin-3-yl)-2-oxoindoline-5-carbonitrile weredissolved in 50 ml of dichloromethane. Under an atmosphere of nitrogen,14 ml (98.11 mmol) of a 7 N methanolic ammonia solution were slowlyadded dropwise to the cooled reaction solution. The colour of thesolution changed to light-yellow, and the solution was stirred at roomtemperature overnight, during which time the product slowly crystallizedout. The course of the reaction was monitored by TLC (silica gel,dichloromethane/methanol in a ratio of 9:1). The solvent was removedunder reduced pressure, and the residue was once more taken up anddissolved in dichloromethane. The mixture was then extracted with water.The phases were separated, and a greasy phase which had formed betweenthe phases was added to the aqueous phase. The aqueous phase wasextracted with ethyl acetate until the greasy phase had gone intosolution. All organic phases obtained were combined, and the solvent wasremoved under reduced pressure. The residue was triturated with diethylether, resulting in the formation of a solid substance which wasfiltered off and dried in a vacuum drying cabinet at moderatetemperature (35° C.). This gave 4.54 g (15.43 mmol, 85%) of the3-amino-3-(2-ethoxypyridin-3-yl)-2-oxoindoline-5-carbonitrile as asolid.

ESI-MS [M+H⁺]=295.3 calculated for C₁₆H₁₄N₄O₂=294.32

1e)3-Amino-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxoindoline-5-carbonitrile

3.54 g (12.03 mmol) of3-amino-3-(2-ethoxypyridin-3-yl)-2-oxoindoline-5-carbonitrile weredissolved in 80 ml of anhydrous dimethylformamide (dried over molecularsieve). Under an atmosphere of nitrogen and with cooling using anice-bath, 1.49 g (13.23 mmol) of potassium tert-butoxide were added alittle at a time. The colour of the reaction mixture changed, and thebrown solution was stirred at 0° C. for another hour to ensure that thedeprotonation proceeded to completion. At low temperature, 3.16 g (13.23mmol) 2,4-dimethoxybenzenesulphonyl chloride were added, and the mixturewas stirred at 0° C. for another two hours. The course of the reactionwas monitored by TLC (silica gel, dichloromethane/methanol in a ratio of9:1). The reaction mixture was poured into ice-water and then extractedwith ethyl acetate. The organic phase was washed with saturated sodiumchloride solution and dried over magnesium sulphate, and the solvent wasevaporated. The residue was suspended in diethyl ether and stirred untilthe product precipitated as a solid and could be removed by filtration.After removal of the solvent, the mother liquor was once more treatedwith diethyl ether (2×) until finally, after drying, 4.67 g (9.44 mmol,79%) of the desired3-amino-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxoindoline-5-carbonitrilewere obtained as a solid substance.

ESI-MS [M+H⁺]=495.15 calculated for C₂₄H₂₂N₄O₆S=494.53

1f) Phenyl[5-cyano-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carbamate

4.67 g (9.44 mmol) of3-amino-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxoindoline-5-carbonitrilewere dissolved in 120 ml of pyridine and cooled to 0° C. using anice-bath. 1.30 ml (10.39 mmol) of neat phenyl chloroformate were added,and the reaction mixture was stirred at 0° C. for 2 hours. The course ofthe reaction was monitored by TLC (silica gel, dichloromethane/methanolin a ratio of 95:5). The solvent and especially pyridine were removedunder reduced pressure, and the residue was diluted with water andextracted with ethyl acetate (3×). The combined organic phases werewashed with saturated sodium chloride solution, dried over magnesiumsulphate and filtered, and the solvent was removed under reducedpressure. Traces of pyridine were removed by repeated addition oftoluene and evaporation on a rotary evaporator. Diethyl ether was addedto the isolated residue, and a solid crystallized overnight giving 5.62g (9.14 mmol, 97%) of the desired product phenyl[5-cyano-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indole-3-yl]carbamate.

ESI-MS [M+H⁺]=615.15 calculated for O₃₁H₂₆N₄O₈S=614.64

1g)N-[5-Cyano-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(1-methylpiperidin-4-yl)piperazine-1-carboxamide

1.00 g (1.63 mmol) of phenyl[5-cyano-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carbamate,596 mg (3.25 mmol) of 1-(1-methylpiperidin-4-yl)piperazine and 8 ml ofdried THF were combined and the mixture was stirred at room temperaturefor 24 hours. The end of the reaction was detected with the aid ofanalytical HPLC (RP, eluents acetonitrile/water, 0.01% TFA). The solventwas removed, and the residue was purified by preparative HPLC usingdichloromethane and 6% methanol as eluents on a Chromolith column(normal phase, from Merck). After repeated column chromatography, it waspossible to isolate 230 mg (0.33 mmol, 21%) of theN-[5-cyano-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(1-methylpiperidin-4-yl)piperazine-1-carboxamide.Alternatively, work-up and purification after the reaction had endedcould be carried out as follows: the solvent was removed. The crudematerial was dissolved in ethyl acetate and extracted with 1 N HCl. Theimpurities were detected in the organic phase, the product being in theacidic aqueous phase. Accordingly, the aqueous phase was neutralizedwith 2 N NaOH solution and extracted with ethyl acetate. After dryingover magnesium sulphate, filtration and removal of the ethyl acetateunder reduced pressure, the product could be crystallized with diethylether. TheN-[5-cyano-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(1-methylpiperidin-4-yl)piperazine-1-carboxamidewas obtained in yields of >50%.

ESI-MS [M+H⁺]=704.2 calculated for C₃₅H₄₁N₇O₇S=703.82

¹H-NMR ([D6]-DMSO, 400 MHz) δ [ppm]=8.12 (d, 1H, J=4.8 Hz), 7.88 (d, 1H,J=8.8 Hz), 7.87 (d, 1H, J=8.7 Hz), 7.81 (d, 1H, J=8.5 Hz), 7.72 (d, 1H,J=7.6 Hz), 7.67 (s, 1H), 7.64 (s, 1H), 7.02 (dd, 1H, J=5.0 Hz, J=7.5Hz), 6.69 (d, 1H, J=8.9 Hz), 6.65 (s, 1H), 4.15 (m, 2H), 3.85 (s, 3H),3.44 (s, 3H), 3.20 (m, 4H), 2.76 (m, 2H, J=11.1 Hz), 2.34 (m, 4H), 2.11(m, 4H), 1.81 (m, 2H, J=11.3 Hz), 1.64 (m, 2H, J=10.7 Hz), 1.37 (m, 2H),1.06 (t, 1H, J=7.0 Hz).

Example 5N-[5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulphonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl}-4-(1-methylpiperidin-4-yl)piperazine-1-carboxamide5a) Phenyl5-cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-3-[(phenoxycarbonyl)amino]-indoline-2-carboxylate

2.78 g (9.43 mmol) of3-amino-3-(2-ethoxypyridin-3-yl)-2-oxoindoline-5-carbonitrile (preparedaccording to Example 1, process steps 1a) to 1c)) were suspended in 25ml of dichloromethane and cooled with an ice-bath to 0° C. 7.63 ml(94.34 mmol) of pyridine were added, and 2.37 ml (18.87 mmol) of phenylchloroformate were then added slowly dropwise such that the temperaturedid not exceed 5-10° C. With thawing of the ice-bath, the reaction wasstirred at room temperature overnight, and a lightly coloured solidprecipitated out. The reaction mixture was diluted with dichloromethane,and after addition of water, the solid went back into solution. Thephases were separated and the aqueous phase was again extracted withdichloromethane (1×). The combined organic phases were washed initiallywith water (3×) and then with saturated sodium chloride solution (1×).After drying over magnesium sulphate, filtration and evaporation of thesolvent under reduced pressure, the residue was subjected to incipientdissolution in diethyl ether, and 10 times the amount of pentane wasadded. A white precipitate formed, and this was filtered off withsuction, washed with pentane and dried in a vacuum drying cabinet at 40°C. After fractional crystallization, a total of 4.46 g (8.35 mmol, 89%)of phenyl5-cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-3-[(phenyloxycarbonyl)amino]indoline-1-carboxylatewere isolated.

ESI-MS [M+H⁺]=535.15 calculated for C₃₀H₂₂N₄O₆=534.53

5b)N-[5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(1-methylpiperidin-4-yl)piperazine-1-carboxamide

760 mg (1.42 mmol) of phenyl5-cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-3-[(phenoxy-carbonyl)amino]indoline-1-carboxylatewere initially charged in 5 ml of THF, and 1.42 g (5.69 mmol) of1-(1-methylpiperidin-4-yl)piperazine were added undiluted at roomtemperature. The reaction mixture was stirred overnight, and thereaction was checked by TLC (silica gel, dichloromethane/methanol 15:5)to determine the progress of the reaction. The reaction was diluted withethyl acetate and washed with water (1×) and saturated sodium chloridesolution (1×). The organic phase was dried over magnesium sulphate andfiltered, and the solvent was removed under reduced pressure. Theresidue was taken up in a little diethyl ether, and 6 times the amountof cyclohexane was added. A colourless solid comprising 615 mg (1.22mmol, 86%) of pureN-[5-cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(1-methylpiperidin-4-yl)piperazine-1-carboxamideprecipitated out.

ESI-MS [M+H⁺]=504.25 calculated for C₂₇H₃₃N₇O₃=503.61

5c)N-[5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulphonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(1-methylpiperidin-4-yl)piperazine-1-carboxamide

80.0 mg (0.16 mmol) ofN-[5-cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(1-methylpiperidin-4-yl)piperazine-1-carboxamidewere dissolved in dimethylformamide, and 7.63 mg (0.19 mmol, 60% w/w) ofsodium hydride were added at 0° C. For the deprotonation of the1,3-dihydro-2H-indol-2-on derivative, the mixture was stirred for 10minutes, and 39.4 mg (0.19 mmol) of 4-methoxybenzenesulphonyl chloridewere then added. The mixture was then allowed to warm to roomtemperature and stirred for 30 minutes. The progress of the reaction wasmonitored by TLC (silica gel, dichloromethane/methanol 1:1). Saturatedsodium bicarbonate solution and ethyl acetate were added to the reactionmixture, and the phases were then separated. The aqueous phase wasreextracted with ethyl acetate (1×). The combined organic phase waswashed with water (1×) and saturated sodium chloride solution (1×),dried over magnesium sulphate and filtered, and the solvent was removedunder reduced pressure. The residue was purified by preparative MPLC(ISCO Companion, 4 g NP cartridge) using the mobile phasesdichloromethane/methanol (5-20%). What was isolated were 27.3 mg (0.04mmol, 23% yield, 90% purity) ofN-[5-cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulphonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(1-methylpiperidin-4-yl)piperazine-1-carboxamide.

ESI-MS [M+H⁺]=674.2 calculated for C₃₄H₃₉N₇O₆S=673.80

Alternative purification methods to the crystallization of the crudemixtures include the conventional column chromatography on a normalphase (NP-SiO₂ cartridge, Chromabond) using the mobile phasesdichloromethane/methanol and the preparative HPLC (RP, mobile phaseacetonitrile/water, 0.01% TFA or 0.01% acetic acid).

Examples 2 to 4 and 6 to 30

The compounds according to Examples 2 to 4 and 6 to 30 can be preparedin a manner analogous to the preparation procedures according to Example1 and/or Example 5 using the appropriate starting materials.

Example 2N-{5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulphonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl}-4-(1-methylpiperidin-4-yl)piperazine-1-carboxamide

ESI-MS [M+H⁺]=674.05 calculated for C₃₄H₃₉N₇O₆S=673.80

Example 3N-[5-Cyano-1-[(2-ethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(1-methylpiperidin-4-yl)piperazine-1-carboxamidetrifluoroacetate

ESI-MS [M+H⁺]=688.3 calculated for C₃₅H₄₁N₇O₆S=687.82

Example 4N-[5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulphonyl)-2,3-dihydro-1H-indol-3-yl]-4-(1-methylpiperidin-4-yl)piperazine-1-carboxamide

ESI-MS [M+H⁺]=644.2 calculated for C₃₃H₃₇N₇O₅S=643.77

Example 31N-[5-Cyano-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(4-methylpiperazin-1-yl)piperidine-1-carboxamide

100 mg (0.16 mmol) of the phenyl[5-cyano-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carbamate(prepared according to Example 1, process steps 1a) to 1f)) wereinitially charged in 8 ml of anhydrous tetrahydrofuran (dried overmolecular sieve), and 44.7 mg (0.24 mmol) of1-methyl-4-(piperidin-4-yl)piperazine were added. The reaction mixturewas stirred at room temperature overnight. The course of the reactionwas monitored by TLC (silica gel, dichloromethane/methanol in a ratio of9:1) and LCMS (RP, acetonitrile/water as eluents and 0.01% TFA). Thesolvent was removed under reduced pressure, and the residue was taken upin dichloromethane and extracted with 2 N sodium hydroxide solution(1×). The combined organic phases were dried over magnesium sulphate andfiltered, and the solvent was removed under reduced pressure. The crudemixture was purified twice by column chromatography (5 g NP-SiO₂cartridge Chromabond) using dichloro-methane/methanol in a ratio of 99:1to 80:20 as eluent. What was isolated were 53.8 mg (0.08 mmol, 47%) ofpureN-[5-cyano-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(4-methylpiperazin-1-yl)piperidine-1-carboxamide.

ESI-MS [M+H⁺]=704.25 calculated for C₃₅H₄₁N₇O₇S=703.82

¹H-NMR ([D6]-DMSO, 400 MHz) δ [ppm]=8.13 (dd, 1H, J=1.4 Hz, J=4.8 Hz),7.88 (d, 1H, J=8.5 Hz), 7.87 (d, 1H, J=8.8 Hz), 7.81 (dd, 1H, J=1.6 Hz,J=8.6 Hz), 7.71 (dd, 1H, J=1.4 Hz, J=7.6 Hz), 7.68 (d, 1H, J=1.3 Hz),7.65 (s, 1H), 7.02 (dd, 1H, J=4.9 Hz, J=7.6 Hz), 6.68 (d, 1H, J=8.9 Hz),6.65 (s, 1H), 4.17 (m, 2H), 3.85 (s, 3H), 3.80 (m, 2H), 3.44 (s, 3H),2.62 (m, 2H), 2.41-2.12 (m, 9H), 2.12 (s, 3H), 1.61 (m, 2H), 1.16 (m,2H), 1.09 (t, 3H, J=7.0 Hz).

Examples 32 to 36

The compounds according to Examples 32 to 36 can be prepared in a manneranalogous to the preparation procedures according to Example 1, 5 and/or31 using the appropriate starting materials.

Example 32N-[5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulphonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(4-methylpiperazin-1-yl)piperidine-1-carboxamide

ESI-MS [M+H⁺]=674.8 calculated for C₃₄H₃₉N₇O₆S=673.80

Example 33N-[5-Cyano-1-[(2-ethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(4-methylpiperazin-1-yl)piperidine-1-carboxamidetrifluoroacetate

ESI-MS [M+H⁺]=688.2 calculated for C₃₅H₄₁N₇O₆S=687.82

Example 34N-[5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulphonyl)-2,3-dihydro-1H-indol-3-yl]-4-(4-methylpiperazin-1-yl)piperidine-1-carboxamide

ESI-MS [M+H⁺]=644.7 calculated for C₃₃H₃₇N₇O₅S=643.77

Example 35N-[5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulphonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(4-methylpiperazin-1-yl)piperidine-1-carboxamidetrifluoroacetate

ESI-MS [M+H⁺]=674.2 calculated for C₃₄H₃₉N₇O₆S=673.80

Example 37N-[5-Cyano-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(4-ethylpiperazin-1-yl)piperidine-1-carboxamide

100 mg (0.16 mmol) of the phenyl[5-cyano-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carbamate(prepared according to Example 1, process steps 1a) to 1f)), dissolvedin 8 ml of anhydrous tetrahydrofuran (dried over molecular sieve) wereinitially charged. 74.9 mg (0.24 mmol) of1-ethyl-4-piperidin-4-ylpiperazine and 0.07 ml of triethylamine wereadded together to the reaction mixture, which was then stirred at roomtemperature overnight. To accelerate the reaction and to achievecomplete conversion, the mixture was again heated to 50° C. The courseof the reaction was monitored by TLC (silica gel,dichloromethane/methanol in a ratio of 9:1) and LCMS (RP,acetonitrile/water as eluents and 0.01% TFA). The solvent was removedunder reduced pressure, and the residue was taken up in dichloromethaneand extracted with 2 N sodium hydroxide solution (1×). The combinedorganic phases were dried over magnesium sulphate and filtered, and thesolvent was removed under reduced pressure. The crude mixture waspurified initially by column chromatography of silica gel (column 20×200mm) using dichloromethane and 2% methanol as eluents. The combined,still slightly contaminated product fractions were purified again bypreparative HPLC on a Chromolith column (normal phase, from Merck) usingthe eluents dichloromethane and methanol (gradient 0-10% by volume ofmethanol over 15 min.). This gave 20 mg (0.03 mmol, 17%) of the desiredN-[5-cyano-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(4-ethylpiperazin-1-yl)piperidine-1-carboxamide.

ESI-MS [M+H⁺]=718.25 calculated for C₃₆H₄₃N₇O₇S=717.85

¹H-NMR ([D6]-DMSO, 400 MHz) δ [ppm]=8.13 (dd, 1H, J=1.2 Hz, J=4.6 Hz),7.88 (d, 1H, J=8.2 Hz), 7.87 (d, 1H, J=8.7 Hz), 7.81 (dd, 1H, J=1.4 Hz,J=8.6 Hz), 7.72 (dd, 1H, J=1.3 Hz, J=7.6 Hz), 7.68 (d, 1H, J=1.1 Hz),7.66 (s, 1H), 7.02 (dd, 1H, J=4.9 Hz, J=7.6 Hz), 6.68 (dd, 1H, J=2.0 Hz,J=8.8 Hz), 6.65 (d, 1H, J=2.2 Hz), 4.17 (m, 2H), 3.85 (s, 3H), 3.81 (m,2H), 3.44 (s, 3H), 2.62 (m, 2H), 2.43-2.29 (m, 11H), 1.61 (m, 2H), 1.15(m, 2H), 1.09 (t, 3H, J=7.0 Hz), 0.97 (t, 3H, J=7.1 Hz).

Examples 38 to 90

The compounds according to Examples 38 to 90 can be prepared in a manneranalogous to the preparation procedures according to Examples 1, 5, 31,37, 55, 61 and/or 67 using the appropriate starting materials.

Example 40N-[5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulphonyl)-2,3-dihydro-1H-indol-3-yl]-4-(4-ethylpiperazin-1-yl)piperidine-1-carboxamide

ESI-MS [M+H⁺]=658.25 calculated for C₃₄H₃₉N₇O₅S=657.79

Example 43N-[5-Cyano-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(4-propylpiperazin-1-yl)piperidine-1-carboxamide

ESI-MS [M+H⁺]=732.3 calculated for C₃₇H₄₅N₇O₇S=731.88

Example 55N-[5-Cyano-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-piperazin-1-ylpiperidine-1-carboxamide55a) tert-Butyl4-[1-({[5-cyano-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]amino}carbonyl)piperidin-4-yl]piperazine-1-carboxylate

100 mg (0.16 mmol) of phenyl[5-cyano-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carbamate(prepared according to Example 1, process steps 1a) to 1f)) wereinitially charged in 8 ml of anhydrous tetrahydrofuran (dried overmolecular sieve), and 65.8 mg (0.24 mmol) of tert-butyl4-piperidin-4-ylpiperazine-1-carboxylate were added. The mixture wasthen stirred at room temperature overnight. The progress of the reactionwas monitored by TLC (silica gel, CH₂Cl₂/MeOH 9:1) and LCMS (RP, mobilephases acetonitrile/water and 0.01% TFA). The solvent was removed underreduced pressure, and the residue was taken up in dichloromethane andextracted with 2 N aqueous sodium hydroxide solution (1×). The combinedorganic phases were dried over magnesium sulphate and filtered, and thesolvent was removed under reduced pressure. The crude mixture waspurified by column chromatography (5 g NP-SiO₂ cartridge, Chromabond)using dichloromethane/methanol in a ratio of 98:2 as mobile phase. Thisgave 55.3 mg (0.07 mmol, 43%) of the desired product, which was directlyused in the next reaction step for Boc deprotection.

ESI-MS [M+H⁺]=790.30 calculated for C₃₉H₄₇N₇O₉S=789.91

55b)N-[5-Cyano-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-piperazin-1-ylpiperidine-1-carboxamide

55.3 mg (0.07 mmol) of tert-butyl4-[1-({[5-cyano-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3,-dihydro-1H-indol-3-yl]amino}carbonyl)piperidin-4-yl]piperazine-1-carboxylatewere initially charged in 4 ml of methanol, and 1.0 ml of 5-6 Mhydrochloric acid in isopropanol was added. The mixture was stirred atroom temperature. The progress of the reaction was monitored by TLC(silica gel, CH₂Cl₂/MeOH 9:1). After complete conversion, the alcoholicsolvent residues were removed, and the residue was taken up indichloromethane and, using 1 N aqueous sodium hydroxide solution,adjusted by extraction to pH 9. The organic phase was separated from theaqueous phase, and the aqueous phase was reextracted withdichloromethane (2×). The combined organic phase was dried overmagnesium sulphate, and the solvent was removed under reduced pressure.The residue was crystallized from diethyl ether. Alternatively, theresidue can also be purified either by conventional columnchromatography on a normal phase (NP-SiO₂ cartridge, Chromabond) usingdichloromethane/methanol as mobile phases or by preparative HPLC (RP,mobile phases acetonitrile/water, 0.01% TFA). After crystallization,15.9 mg (0.023 mmol, 33%) ofN-[5-cyano-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-piperazin-1-ylpiperidine-1-carboxamidewere isolated.

ESI-MS [M+H⁺]=690.45 calculated for C₃₄H₃₉N₇O₇S=689.80

Examples 25 to 30 and 56 to 60 and 85 to 90

The compounds according to Examples 25 to 30 and 56 to 60 and 85 to 90can also be prepared in a manner analogous to the preparation proceduresaccording to Examples 1, 5, 31, 37 and/or 55 using the appropriatestarting materials.

Example 25N-[5-Cyano-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-piperidin-4-ylpiperazine-1-carboxamidebis(trifluoroacetate)

ESI-MS [M+H⁺]=690.15 calculated for C₃₄H₃₉N₇O₇S=689.80

Example 85N-[5-Cyano-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4,4′-bipiperidine-1-carboxamidebis(trifluoroacetate)

ESI-MS [M+H⁺]=689.25 calculated for C₃₅H₄₀N₆O₇S=688.81

In the compounds (I) according to the invention, the substituent R7 can,according to synthesis scheme 1 or 2, also be introduced subsequently byreductive amination, which is to be illustrated in an exemplary mannerusing Examples 61 and 67:

Example 61N-[5-Cyano-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-1′-methyl-4,4′-bipiperidine-1-carboxamide

100 mg (0.138 mmol) of4-[1-({[5-cyano-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]amino}carbonyl)piperidin-4-yl]piperidiniumchloride (corresponds to the chloride salt of Example 85) (preparedaccording to Example 1, process steps 1a) to 1f) and Example 55, processsteps 55a) to 55b)) were initially introduced in 10 ml ofdichloromethane. 20 μl (0.207 mmol) of aqueous formaldehyde solution(37% strength) were added, and the reaction mixture was stirred for 5minutes. The solution became slightly turbid. 98 mg (0.69 mmol) ofsodium sulphate and 20 μl (0.279 mmol) of glacial acetic acid wereadded, and the mixture was stirred for 1.5 h. 48.7 mg (0.207 mmol) ofthe hydrogenation reagent sodium acetoxyborohydride were introduced alittle at a time, and after 15 minutes the reaction mixture became clearand then soon turbid again. The mixture was stirred at room temperatureovernight and warmed to 40° C. for another hour. The reaction mixturewas initially diluted with 30 ml of dichloromethane and then extractedwith saturated sodium bicarbonate solution (3×). The combined organicphases were dried over magnesium sulphate and filtered, and the solventwas evaporated under reduced pressure. What was isolated were 75 mg ofcrude product which was purified by a preparative HPLC on a Chromolithcolumn (RP-18e, from Merck, mobile phases acetonitrile/water, 0.01%acetic acid). What was isolated were 5 mg (0.007 mmol, 5%) of thedesiredN-[5-cyano-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-1′-methyl-4,4′-bipiperidine-1-carboxamide(proportionally present as acetate salt).

ESI-MS [M+H⁺]=703.2 calculated for C₃₆H₄₂N₆O₇S=702.83

Example 67N-[5-Cyano-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-1′-ethyl-4,4′-bipiperidine-1-carboxamidetrifluoroacetate

ESI-MS [M+H⁺]=717.30 calculated for C₃₇H₄₄N₆O₇S=716.86

RACEMATE RESOLUTION of the racemic compounds according to EXAMPLES 1 to90:

In an exemplary manner, using Example 1, the separation of the racematesinto its enantiomers (Example 1A and 1B) by separation on a preparativechiral column is shown:

A.) Racemate Resolution of the Racemic Compound According to Example 1:

100 mg (0.14 mmol) of the racemicN-[5-cyano-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(1-methylpiperidin-4-yl)piperazine-1-carboxamide(EXAMPLE 1) were separated on a chiral preparative column (ChiralcellOD, flow rate 55 ml/min) using n-heptane/ethanol (700:300) as eluent.The enantiomer which eluted first, having a positive optical rotation(Example 1A), could be isolated in a yield of 19 mg (0.03 mmol, 19%) andthe enantiomer which followed, having a negative optical rotation(Example 1B), could be isolated in a yield of 8 mg (0.01 mmol, 8%).

Example 1A(+)-N-[5-Cyano-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(1-methylpiperidin-4-yl)piperazine-1-carboxamide

ESI-MS [M+H⁺]=704.25 calculated for C₃₅H₄₁N₇O₇S=703.82

HPLC (Chiralcel OD 0.46 cm×25 cm; n-heptane/ethanol 7:3) R_(f)=9.04 minOptical rotation α (22° C., 589 nm, CHCl₃, 1 mg/ml)=dextrorotatory

¹H-NMR ([D6]-DMSO, 500 MHz) δ [ppm]=8.13 (dd, 1H, J=1.6 Hz, J=4.9 Hz),7.89 (d, 1H, J=8.9 Hz), 7.88 (d, 1H, J=8.6 Hz), 7.82 (dd, 1H, J=1.7 Hz,J=8.6 Hz), 7.72 (dd, 1H, J=1.5 Hz, J=7.7 Hz), 7.68 (d, 1H, J=1.6 Hz),7.65 (s, 1H), 7.02 (dd, 1H, J=4.9 Hz, J=7.6 Hz), 6.69 (dd, 1H, J=2.2 Hz,J=8.9 Hz), 6.66 (d, 1H, J=2.1 Hz), 4.17 (m, 2H), 3.86 (s, 3H), 3.45 (s,3H), 3.21 (m, 4H), 2.77 (m, 2H, J=11.0 Hz), 2.34 (m, 4H), 2.12 (m, 4H),1.82 (m, 2H, J=10.9 Hz), 1.64 (m, 2H, J=10.8 Hz), 1.37 (m, 2H), 1.08 (t,3H, J=7.0 Hz).

Example 1B(−)-N-[5-Cyano-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(1-methylpiperidin-4-yl)piperazine-1-carboxamide

ESI-MS [M+H⁺]=704.25 calculated for C₃₅H₄₁N₇O₇S=703.82 HPLC (ChiralcelOD 0.46 cm×25 cm; n-heptane/ethanol 7:3) R_(f)=25.73 min Opticalrotation α (22° C., 589 nm, CHCl₃, 1 mg/ml)=laevorotatory

¹H-NMR ([D6]-DMSO, 500 MHz) δ [ppm]=8.13 (dd, 1H, J=1.2 Hz, J=4.7 Hz),7.88 (d, 1H, J=8.9 Hz), 7.87 (d, 1H, J=8.5 Hz), 7.81 (dd, 1H, J=1.5 Hz,J=8.5 Hz), 7.72 (dd, 1H, J=1.1 Hz, J=7.6 Hz), 7.68 (s, 1H), 7.64 (s,1H), 7.01 (dd, 1H, J=4.9 Hz, J=7.6 Hz), 6.69 (dd, 1H, J=1.9 Hz, J=9.0Hz), 6.66 (d, 1H, J=1.9 Hz), 4.16 (m, 2H), 3.85 (s, 3H), 3.45 (s, 3H),3.20 (m, 4H), 2.77 (m, 2H, J=11.5 Hz), 2.34 (m, 4H), 2.12 (m, 4H), 1.82(m, 2H, J=11.3 Hz), 1.64 (m, 2H, J=11.5 Hz), 1.37 (m, 2H), 1.07 (t, 3H,J=7.0 Hz).

B.) Racemate Resolution of the Racemic Compound According to Example 31:

N-[5-Cyano-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(4-methylpiperazin-1-yl)piperidine-1-carboxamide(EXAMPLE 31) was separated on a chiral preparative column (ChiralcellOD, flow rate 55 ml/min) using n-heptane/ethanol (700:300) as eluent.The enantiomer which eluted first has a positive optical rotation(Example 31A), and the enantiomer which followed had a negative opticalrotation (Example 31B).

Example 31A(+)—N-[5-Cyano-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(4-methylpiperazin-1-yl)piperidine-1-carboxamide

ESI-MS [M+H⁺]=704.80 calculated for C₃₅H₄₁N₇O₇S=703.82

HPLC (Chiralcel OD 0.46 cm×25 cm; n-heptane/ethanol 7:3) R_(f)=9.60 minOptical rotation α (22° C., 589 nm, CHCl₃, 1 mg/ml)=dextrorotatory

¹H-NMR ([D6]-DMSO, 500 MHz) δ [ppm]=8.12 (dd, 1H, J=1.6 Hz, J=4.8 Hz),7.87 (d, 1H, J=8.5 Hz), 7.86 (d, 1H, J=8.8 Hz), 7.81 (dd, 1H, J=1.7 Hz,J=8.6 Hz), 7.73 (dd, 1H, J=1.5 Hz, J=7.7 Hz), 7.69 (s, 1H), 7.67 (d, 1H,J=1.5 Hz), 7.02 (dd, 1H, J=4.9 Hz, J=7.6 Hz), 6.67 (dd, 1H, J=2.2 Hz,J=8.9 Hz), 6.65 (d, 1H, J=2.1 Hz), 4.14 (m, 2H), 3.83 (s, 3H), 3.80 (m,2H), 3.42 (s, 3H), 2.60 (m, 2H), 2.39-2.10 (m, 9H), 2.10 (s, 3H), 1.60(m, 2H), 1.12 (m, 2H), 1.06 (t, 3H, J=7.0 Hz).

Example 31B(−)-N-[5-Cyano-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(4-methylpiperazin-1-yl)piperidine-1-carboxamide

ESI-MS [M+H⁺]=704.80 calculated for C₃₅H₄₁N₇O₇S=703.82 HPLC (ChiralcelOD 0.46 cm×25 cm; n-heptane/ethanol 7:3) R_(f)=34.31 min Opticalrotation α (22° C., 589 nm, CHCl₃, 1 mg/ml)=laevorotatory

¹H-NMR ([D6]-DMSO, 500 MHz) δ [ppm]=8.12 (dd, 1H, J=1.6 Hz, J=4.9 Hz),7.86 (d, 1H, J=8.7 Hz), 7.85 (d, 1H, J=8.8 Hz), 7.81 (dd, 1H, J=1.6 Hz,J=8.6 Hz), 7.72 (dd, 1H, J=1.4 Hz, J=7.6 Hz), 7.69 (s, 1H), 7.67 (d, 1H,J=1.6 Hz), 7.02 (dd, 1H, J=4.9 Hz, J=7.6 Hz), 6.67 (dd, 1H, J=2.2 Hz,J=8.9 Hz), 6.64 (d, 1H, J=2.0 Hz), 4.13 (m, 2H), 3.83 (s, 3H), 3.80 (m,2H), 3.42 (s, 3H), 2.60 (m, 2H), 2.42-2.10 (m, 9H), 2.10 (s, 3H), 1.60(m, 2H), 1.12 (m, 2H), 1.06 (t, 3H, J=7.0 Hz).

C.) Racemate Resolution of the Racemic Compound According to Example 37:

N-[5-Cyano-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(4-ethylpiperazin-1-yl)piperidine-1-carboxamide(EXAMPLE 37) was separated on a chiral preparative column (ChiralcellOD, flow rate 55 ml/min) using n-heptane/ethanol (700:300) as eluent.The enantiomer which eluted first had a positive optical rotation(Example 37A), and the enantiomer which followed had a negative opticalrotation (Example 37B).

Example 37A(+)-N-[5-Cyano-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(4-ethylpiperazin-1-yl)piperidine-1-carboxamide

ESI-MS [M+H⁺]=718.30 calculated for C₃₆H₄₃F₃N₇O₇S=717.85

HPLC (Chiralcel OD 0.46 cm×25 cm; n-heptane/ethanol 7:3) R_(f)=7.29 minOptical rotation α (22° C., 589 nm, CHCl₃, 1 mg/ml)=dextrorotatory

¹H-NMR ([D6]-DMSO, 500 MHz) δ [ppm]=8.13 (dd, 1H, J=1.7 Hz, J=4.9 Hz),7.89 (d, 1H, J=8.6 Hz), 7.88 (d, 1H, J=8.8 Hz), 7.82 (dd, 1H, J=1.8 Hz,J=8.6 Hz), 7.72 (dd, 1H, J=1.7 Hz, J=7.7 Hz), 7.69 (d, 1H, J=1.7 Hz),7.67 (s, 1H), 7.02 (dd, 1H, J=4.9 Hz, J=7.7 Hz), 6.69 (dd, 1H, J=2.2 Hz,J=8.9 Hz), 6.66 (d, 1H, J=2.2 Hz), 4.18 (m, 2H), 3.85 (s, 3H), 3.81 (m,2H), 3.44 (s, 3H), 2.62 (m, 2H), 2.42-2.24 (m, 11H), 1.62 (m, 2H), 1.15(m, 2H), 1.09 (t, 3H, J=7.1 Hz), 0.96 (t, 3H, J=7.2 Hz).

Example 37B(−)—N-[5-Cyano-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(4-ethylpiperazin-1-yl)piperidine-1-carboxamideESI-MS [M+H⁺]=718.25 calculated for C₃₆H₄₃F₃N₇O₇S=717.85

HPLC (Chiralcel OD 0.46 cm×25 cm; n-heptane/ethanol 7:3) R_(f)=12.41 minOptical rotation α (22° C., 589 nm, CHCl₃, 1 mg/ml)=laevorotatory

¹H-NMR ([D6]-DMSO, 500 MHz) δ [ppm]=8.12 (dd, 1H, J=1.6 Hz, J=4.9 Hz),7.88 (d, 1H, J=8.5 Hz), 7.87 (d, 1H, J=8.8 Hz), 7.80 (dd, 1H, J=1.7 Hz,J=8.6 Hz), 7.71 (dd, 1H, J=1.5 Hz, J=7.7 Hz), 7.68 (d, 1H, J=1.5 Hz),7.66 (s, 1H), 7.00 (dd, 1H, J=4.9 Hz, J=7.6 Hz), 6.67 (dd, 1H, J=2.2 Hz,J=8.9 Hz), 6.65 (d, 1H, J=2.1 Hz), 4.16 (m, 2H), 3.84 (s, 3H), 3.80 (m,2H), 3.44 (s, 3H), 2.61 (m, 2H), 2.41-2.23 (m, 11H), 1.60 (m, 2H), 1.14(m, 2H), 1.08 (t, 3H, J=7.1 Hz), 0.95 (t, 3H, J=7.2 Hz).

D.) Racemate Resolution of the Racemic Compounds 2 to 30, 21 to 36 and38 to 90:

In a manner analogous to the racemate resolutions of the racemiccompounds 1, 31 and 37, it is possible to carry out the separation ofthe racemates 2 to 30, 32 to 36 and 38 to 90 give the corresponding(+)-enantiomers 2A, 3A, 4A, 5A, 6A, 7A, 8A, 9A, 10A, 11A, 12A, 13A, 14A,15A, 16A, 17A, 18A, 19A, 20A, 21A, 22A, 23A, 24A, 25A, 26A, 27A, 28A,29A, 30A and 32A, 33A, 34A, 35A and 38A, 39A, 40A, 41A, 42A, 43A, 44A,45A, 46A, 47A, 48A, 49A, 50A, 51A, 52A, 53A, 54A, 55A, 56A, 57A, 58A,59A, 60A, 61A, 62A, 63A, 64A, 65A, 66A, 67A, 68A, 69A, 70A, 71A, 72A,73A, 74A, 75A, 76A, 77A, 78A, 79A, 80A, 81A, 82A, 83A, 84A, 85A, 86A,87A, 88A, 89A and 90A and the corresponding (−)-enantiomers 2B, 3B, 4B,5B, 6B, 7B, 8B, 9B, 10B, 11B, 12B, 13B, 14B, 15B, 16B, 17B, 18B, 19B,20B, 21B, 22B, 23B, 24B, 25B, 26B, 27B, 28B, 29B, 30B and 32B, 33B, 34B,35B and 38B, 39B, 40B, 41B, 42B, 43B, 44B, 45B, 46B, 47B, 48B, 49B, 50B,51B, 52B, 53B, 54B, 55B, 56B, 57B, 58B, 59B, 60B, 61B, 62B, 63B, 64B,65B, 66B, 67B, 68B, 69B, 70B, 71B, 72B, 73B, 74B, 75B, 76B, 77B, 78B,79B, 80B, 81B, 82B, 83B, 84B, 85B, 86B, 87B, 88B, 89B and 90B.

The enantiomers A and B can also be prepared using enantiomerically pureprecursors and intermediates, for example analogously to synthesisschemes 1 or 2, preferably via synthesis scheme 1. The separation of theracemic mixture into the (+)-enantiomers and (−)-enantiomers can becarried out by chiral preparative chromatography, preferably via thecorresponding amine building block VI.

Example 7B(−)—N-[5-Cyano-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(1-ethylpiperidin-4-yl)piperazine-1-carboxamidetrifluoroacetate

ESI-MS [M+H⁺]=718.25 calculated for C₃₆H₄₃N₇O₇S=717.85

Example 40B(−)-N-[5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulphonyl)-2,3-dihydro-1H-indol-3-yl]-4-(4-ethylpiperazin-1-yl)piperidin-1-carboxamide

ESI-MS [M+H⁺]=658.25 calculated for C₃₄H₃₉N₇O₅S=657.79

Example 61B(−)-N-[5-Cyano-1-[(2,4-dimethoxyphenyl)sulphonyl)-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-1′-methyl-4,4′-bipiperidine-1-carboxamidetrifluoroacetate

ESI-MS [M+H⁺]=703.30 calculated for C₃₆H₄₂N₆O₇S=702.83

¹H-NMR ([D6]-DMSO, 500 MHz) δ [ppm]=9.26 (1H, protonation of TFA), 8.12(dd, 1H, J=1.7 Hz, J=4.9 Hz), 7.87 (dd, 2H, J=1.3 Hz, J=8.7 Hz), 7.80(dd, 1H, J=1.8 Hz, J=8.5 Hz), 7.80 (m, 2H), 7.66 (s, 1H), 7.00 (dd, 1H,J=4.9 Hz, J=7.6 Hz), 6.68 (dd, 1H, J=2.2 Hz, J=8.9 Hz), 6.65 (d, 1H,J=2.1 Hz), 4.16 (m, 2H), 3.85 (s, 6H), 3.44-3.41 (m, 5H), 2.85 (m, 2H),2.73 (m, 2H), 2.57 (m, 2H), 1.81 (m, 2H), 1.55 (m, 2H), 1.34-1.22 (m,4H), 1.08 (t, 3H, J=7.0 Hz), 0.92 (m, 2H).

Example 67B(−)—N-[5-Cyano-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-1′-ethyl-4,4′-bipiperidine-1-carboxamidetrifluoroacetate

ESI-MS [M+H⁺]=717.35 calculated for C₃₇H₄₄N₆O₇S=716.86

The amines of the general formula X can be prepared according tosynthesis scheme 1 or 2 by reductive amination. Hereinbelow, this isshown using the preparation of the amine compound1-ethyl-4-piperidin-4-ylpiperazine as an example:

Example 91 1-Ethyl-4-piperidin-4-ylpiperazine 91a) tert-Butyl4-(4-ethylpiperazin-1-yl)piperidine-1-carboxylate

With ice-cooling, 29.2 g (256 mmol) of N-ethylpiperazine and 50.0 g (256mmol) of tert-butyl 4-oxopiperidine-1-carboxylate (corresponds to1-Boc-4-piperidone) were initially charged in 800 ml of ethanol and 15.4g (256 mmol) of glacial acetic acid were added. A little at a time, 16.1g (256 mmol) of sodium acetoxyborohydride was then added to the cooledreaction mixture. Initially, a slight evolution of gas and, after ⅔ ofthe reducing agent had been added, foaming could be observed. Thereaction mixture was stirred at room temperature overnight. For work-up,200 ml of 2 N aqueous sodium hydroxide solution were added with coolingto the reaction solution, the solvent ethanol was distilled off and thereaction mixture which remained was diluted with water. The mixture wasextracted with diethyl ether (2×) and washed with saturated sodiumchloride solution (1×), the combined organic phases were dried overmagnesium sulphate and filtered and the solvent was removed underreduced pressure. The desired product was obtained as a yellow oil whichwas subsequently chromatographed on a 4 I Nutsche filter filled withsilica gel, using dichloromethane and 10% methanol as eluents. This gavea total of 40 g (135 mmol, 53%) of tert-butyl4-(4-ethylpiperazin-1-yl)piperidine-1-carboxylate.

91 b) 1-Ethyl-4-piperidin-4-ylpiperazine as chloride salt

To remove the protective groups, 40 g (135 mmol) of the tert-butyl4-(4-ethylpiperazin-1-yl)piperidine-1-carboxylate were initially chargedin 200 ml of methanol and 1.8 l of dichloromethane, and 100 ml 5-6 M HClsolution in isopropanol were added. The solution became a suspension,and a slight evolution of gas could be observed. The reaction mixturewas stirred at 40° C. (water bath temperature) for one hour and at roomtemperature over the weekend. For complete deprotection to the desiredproduct, another 50 ml of the 5-6 M HCl solution in isopropanol wereadded, and the mixture was stirred at 40° C. The dichloromethane wasdistilled off on a rotary evaporator, and another 200 ml of methanol and30 ml of the 5-6 M HCl solution in isopropanol were added. After onehour of stirring under reflux, a white suspension formed with strongevolution of gas. Subsequently, a low-viscosity suspension was formed,which was cooled to room temperature. The precipitate was filtered offwith suction and washed with methanol and diethyl ether. After drying,36 g (117 mmol, 87%) of 1-ethyl-4-piperidin-4-ylpiperazine were isolatedas chloride salt.

¹H-NMR (D₂O, 400 MHz) δ [ppm]=3.74-3.47 (m, 11H), 3.28 (q, 2H, J=7.3Hz), 3.06 (dt, 2H, J=2.2 Hz, J=13.2 Hz), 2.38 (m, 2H, J=13.6 Hz), 1.89(dq, 2H, J=4.1 Hz, J=13.3 Hz), 1.30 (t, 3H, J=7.3 Hz).

The chemical structures of the compounds according to Examples 1 to 90(racemate) and the corresponding dextrorotatory (+)-enantiomers(Examples Nos. 1 to 90 with the appended letter “A” such as, forexample, 1A, 2A, etc. . . . ) and the corresponding laevorotatory(−)-enantiomers (Example Nos. 1 to 90 with the appended letter “B”, suchas, for example, 1B, 2B, etc. . . . ) are shown in Table 2 below:

TABLE 2 Compounds of the general formula (Ib) where the radicals R5, R6,R7, X2 and X3 have the meanings mentioned below (in each case per row):Exp. IUPAC Name No. X2 X3 R5 R6 R7 (according to ACD-Labs Version 8.00release product version 8.05)  1 N CH methoxy methoxy methyl(±)-N-[5-cyano-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(1-methylpiperidin-4-yl)piperazine-1-carboxamide 1A N CH methoxy methoxy methyl(+)-N-[5-cyano-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(1-methylpiperidin-4-yl)piperazine-1-carboxamide 1B N CH methoxy methoxy methyl(−)-N-[5-cyano-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(1-methylpiperidin-4-yl)piperazine-1-carboxamide 2 N CH methoxy H methyl(±)-N-{5-cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulphonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl}-4-(1-methylpiperidin-4-yl)piperazine-1-carboxamide 2A N CH methoxy H methyl(+)-N-{5-cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulphonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl}-4-(1-methylpiperidin-4-yl)piperazine-1-carboxamide 2B N CH methoxy H methyl(−)-N-{5-cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulphonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl}-4-(1-methylpiperidin-4-yl)piperazine-1-carboxamide 3 N CH ethoxy H methyl(±)-N-[5-cyano-1-[(2-ethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(1-methylpiperidin-4-yl)piperazine-1-carboxamide 3A N CH ethoxy H methyl(+)-N-[5-cyano-1-[(2-ethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(1-methylpiperidin-4-yl)piperazine-1-carboxamide 3B N CH ethoxy H methyl(−)-N-[5-cyano-1-[(2-ethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(1-methylpiperidin-4-yl)piperazine-1-carboxamide 4 N CH H H methyl(±)-N-[5-cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulphonyl)-2,3-dihydro-1H-indol-3-yl]-4-(1-methylpiperidin-4-yl)piperazine-1-carboxamide  4A N CHH H methyl(+)-N-[5-cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulphonyl)-2,3-dihydro-1H-indol-3-yl]-4-(1-methylpiperidin-4-yl)piperazine-1-carboxamide  4B N CHH H methyl(−)-N-[5-cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulphonyl)-2,3-dihydro-1H-indol-3-yl]-4-(1-methylpiperidin-4-yl)piperazine-1-carboxamide  5 N CH Hmethoxy methyl(±)-N-{5-cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulphonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl}-4-(1-methylpiperidin-4-yl)piperazine-1-carboxamide 5A N CH H methoxy methyl(+)-N-{5-cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulphonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl}-4-(1-methylpiperidin-4-yl)piperazine-1-carboxamide 5B N CH H methoxy methyl(−)-N-{5-cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulphonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl}-4-(1-methylpiperidin-4-yl)piperazine-1-carboxamide 6 N CH ethoxy methoxy methyl(±)-N-[5-cyano-1-[(2-ethoxy-4-methoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(1-methylpiperidin-4-yl)piperazine-1-carboxamide 6A N CH ethoxy methoxy methyl(+)-N-[5-cyano-1-[(2-ethoxy-4-methoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(1-methylpiperidin-4-yl)piperazine-1-carboxamide 6B N CH ethoxy methoxy methyl(−)-N-[5-cyano-1-[(2-ethoxy-4-methoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(1-methylpiperidin-4-yl)piperazine-1-carboxamide 7 N CH methoxy methoxy ethyl(±)-N-[5-cyano-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(1-ethylpiperidin-4-yl)piperazine-1-carboxamide 7A N CH methoxy methoxy ethyl(+)-N-[5-cyano-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(1-ethylpiperidin-4-yl)piperazine-1-carboxamide 7B N CH methoxy methoxy ethyl(−)-N-[5-cyano-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(1-ethylpiperidin-4-yl)piperazine-1-carboxamide 8 N CH methoxy H ethyl(±)-N-{5-cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulphonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl}-4-(1-ethylpiperidin-4-yl)piperazine-1-carboxamide 8A N CH methoxy H ethyl(+)-N-{5-cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulphonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl}-4-(1-ethylpiperidin-4-yl)piperazine-1-carboxamide 8B N CH methoxy H ethyl(−)-N-{5-cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulphonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl}-4-(1-ethylpiperidin-4-yl)piperazine-1-carboxamide 9 N CH ethoxy H ethyl(±)-N-[5-cyano-1-[(2-ethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(1-ethylpiperidin-4-yl)piperazine-1-carboxamide 9A N CH ethoxy H ethyl(+)-N-[5-cyano-1-[(2-ethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(1-ethylpiperidin-4-yl)piperazine-1-carboxamide 9B N CH ethoxy H ethyl(−)-N-[5-cyano-1-[(2-ethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(1-ethylpiperidin-4-yl)piperazine-1-carboxamide10 N CH H H ethyl(±)-N-[5-cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulphonyl)-2,3-dihydro-1H-indol-3-yl]-4-(1-ethylpiperidin-4-yl)piperazine-1-carboxamide 10A N CH HH ethyl(+)-N-[5-cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulphonyl)-2,3-dihydro-1H-indol-3-yl]-4-(1-ethylpiperidin-4-yl)piperazine-1-carboxamide 10B N CH HH ethyl(−)-N-[5-cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulphonyl)-2,3-dihydro-1H-indol-3-yl]-4-(1-ethylpiperidin-4-yl)piperazine-1-carboxamide 11 N CH Hmethoxy ethyl(±)-N-{5-cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulphonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl}-4-(1-ethylpiperidin-4-yl)piperazine-1-carboxamide11A N CH H methoxy ethyl(+)-N-{5-cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulphonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl}-4-(1-ethylpiperidin-4-yl)piperazine-1-carboxamide11B N CH H methoxy ethyl(−)-N-{5-cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulphonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl}-4-(1-ethylpiperidin-4-yl)piperazine-1-carboxamide12 N CH ethoxy methoxy ethyl(±)-N-[5-cyano-1-[(2-ethoxy-4-methoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(1-ethylpiperidin-4-yl)piperazine-1-carboxamide12A N CH ethoxy methoxy ethyl(+)-N-[5-cyano-1-[(2-ethoxy-4-methoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(1-ethylpiperidin-4-yl)piperazine-1-carboxamide12B N CH ethoxy methoxy ethyl(−)-N-[5-cyano-1-[(2-ethoxy-4-methoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(1-ethylpiperidin-4-yl)piperazine-1-carboxamide13 N CH methoxy methoxy n-(±)-N-[5-cyano-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-propyl2,3-dihydro-1H-indol-3-yl]-4-(1-propylpiperidin-4-yl)piperazine-1-carboxamide13A N CH methoxy methoxy n-(+)-N-[5-cyano-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-propyl2,3-dihydro-1H-indol-3-yl]-4-(1-propylpiperidin-4-yl)piperazine-1-carboxamide13B N CH methoxy methoxy n-(−)-N-[5-cyano-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-propyl2,3-dihydro-1H-indol-3-yl]-4-(1-propylpiperidin-4-yl)piperazine-1-carboxamide14 N CH methoxy H n-(±)-N-{5-cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulphonyl]-2-oxo-2,3-propyldihydro-1H-indol-3-yl}-4-(1-propylpiperidin-4-yl)piperazine-1-carboxamide14A N CH methoxy H n-(+)-N-{5-cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulphonyl]-2-oxo-2,3-propyldihydro-1H-indol-3-yl}-4-(1-propylpiperidin-4-yl)piperazine-1-carboxamide14B N CH methoxy H n-(−)-N-{5-cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulphonyl]-2-oxo-2,3-propyldihydro-1H-indol-3-yl}-4-(1-propylpiperidin-4-yl)piperazine-1-carboxamide15 N CH ethoxy H n-(±)-N-[5-cyano-1-[(2-ethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-propyldihydro-1H-indol-3-yl]-4-(1-propylpiperidin-4-yl)piperazine-1-carboxamide15A N CH ethoxy H n-(+)-N-[5-cyano-1-[(2-ethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-propyldihydro-1H-indol-3-yl]-4-(1-propylpiperidin-4-yl)piperazine-1-carboxamide15B N CH ethoxy H n-(−)-N-[5-cyano-1-[(2-ethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-propyldihydro-1H-indol-3-yl]-4-(1-propylpiperidin-4-yl)piperazine-1-carboxamide16 N CH H H n-(±)-N-[5-cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulphonyl)-2,3-dihydro-1H-propyl indol-3-yl]-4-(1-propylpiperidin-4-yl)piperazine-1-carboxamide16A N CH H H n-(+)-N-[5-cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulphonyl)-2,3-dihydro-1H-propyl indol-3-yl]-4-(1-propylpiperidin-4-yl)piperazine-1-carboxamide16B N CH H H n-(−)-N-[5-cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulphonyl)-2,3-dihydro-1H-propyl indol-3-yl]-4-(1-propylpiperidin-4-yl)piperazine-1-carboxamide 17N CH H methoxy n-(±)-N-{5-cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulphonyl]-2-oxo-2,3-propyldihydro-1H-indol-3-yl}-4-(1-propylpiperidin-4-yl)piperazine-1-carboxamide17A N CH H methoxy n-(+)-N-{5-cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulphonyl]-2-oxo-2,3-propyldihydro-1H-indol-3-yl}-4-(1-propylpiperidin-4-yl)piperazine-1-carboxamide17B N CH H methoxy n-(−)-N-{5-cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulphonyl]-2-oxo-2,3-propyldihydro-1H-indol-3-yl}-4-(1-propylpiperidin-4-yl)piperazine-1-carboxamide18 N CH ethoxy methoxy n-(±)-N-[5-cyano-1-[(2-ethoxy-4-methoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-propyl2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(1-propylpiperidin-4-yl)piperazine-1-carboxamide18A N CH ethoxy methoxy n-(+)-N-[5-cyano-1-[(2-ethoxy-4-methoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-propyl2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(1-propylpiperidin-4-yl)piperazine-1-carboxamide18B N CH ethoxy methoxy n-(−)-N-[5-cyano-1-[(2-ethoxy-4-methoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-propyloxo-2,3-dihydro-1H-indol-3-yl]-4-(1-propylpiperidin-4-yl)piperazine-1-carboxamide19 N CH methoxy methoxy isopropyl(±)-N-[5-cyano-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(1-isopropylpiperidin-4-yl)piperazine-1-carboxamide19A N CH methoxy methoxy isopropyl(+)-N-[5-cyano-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(1-isopropylpiperidin-4-yl)piperazine-1-carboxamide19B N CH methoxy methoxy isopropyl(−)-N-[5-cyano-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(1-isopropylpiperidin-4-yl)piperazine-1-carboxamide20 N CH methoxy H isopropyl(±)-N-{5-cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulphonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl}-4-(1-isopropylpiperidin-4-yl)piperazine-1-carboxamide20A N CH methoxy H isopropyl(+)-N-{5-cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulphonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl}-4-(1-isopropylpiperidin-4-yl)piperazine-1-carboxamide20B N CH methoxy H isopropyl(−)-N-{5-cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulphonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl}-4-(1-isopropylpiperidin-4-yl)piperazine-1-carboxamide21 N CH ethoxy H isopropyl(±)-N-[5-cyano-1-[(2-ethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(1-isopropylpiperidin-4-yl)piperazine-1-carboxamide21A N CH ethoxy H isopropyl(+)-N-[5-cyano-1-[(2-ethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(1-isopropylpiperidin-4-yl)piperazine-1-carboxamide21B N CH ethoxy H isopropyl(−)-N-[5-cyano-1-[(2-ethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(1-isopropylpiperidin-4-yl)piperazine-1-carboxamide22 N CH H H isopropyl(±)-N-[5-cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulphonyl)-2,3-dihydro-1H-indol-3-yl]-4-(1-isopropylpiperidin-4-yl)piperazine-1-carboxamide 22A NCH H H isopropyl(+)-N-[5-cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulphonyl)-2,3-dihydro-1H-indol-3-yl]-4-(1-isopropylpiperidin-4-yl)piperazine-1-carboxamide 22B NCH H H isopropyl(−)-N-[5-cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulphonyl)-2,3-dihydro-1H-indol-3-yl]-4-(1-isopropylpiperidin-4-yl)piperazine-1-carboxamide 23 NCH H methoxy isopropyl(±)-N-{5-cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulphonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl}-4-(1-isopropylpiperidin-4-yl)piperazine-1-carboxamide23A N CH H methoxy isopropyl(+)-N-{5-cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulphonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl}-4-(1-isopropylpiperidin-4-yl)piperazine-1-carboxamide23B N CH H methoxy isopropyl(−)-N-{5-cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulphonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl}-4-(1-isopropylpiperidin-4-yl)piperazine-1-carboxamide24 N CH ethoxy methoxy isopropyl(±)-N-[5-cyano-1-[(2-ethoxy-4-methoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(1-isopropylpiperidin-4-yl)piperazine-1-carboxamide24A N CH ethoxy methoxy isopropyl(+)-N-[5-cyano-1-[(2-ethoxy-4-methoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(1-isopropylpiperidin-4-yl)piperazine-1-carboxamide24B N CH ethoxy methoxy isopropyl(−)-N-[5-cyano-1-[(2-ethoxy-4-methoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(1-isopropylpiperidin-4-yl)piperazine-1-carboxamide25 N CH methoxy methoxy H(±)-N-[5-cyano-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-piperidin-4-ylpiperazine-1-carboxamide 25AN CH methoxy methoxy H(+)-N-[5-cyano-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-piperidin-4-ylpiperazine-1-carboxamide 25BN CH methoxy methoxy H(−)-N-[5-cyano-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-piperidin-4-ylpiperazine-1-carboxamide 26 NCH methoxy H H(±)-N-{5-cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulphonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl}-4-piperidin-4-ylpiperazine-1-carboxamide 26A N CHmethoxy H H(+)-N-{5-cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulphonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl}-4-piperidin-4-ylpiperazine-1-carboxamide 26B N CHmethoxy H H(−)-N-{5-cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulphonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl}-4-piperidin-4-ylpiperazine-1-carboxamide 27 N CHethoxy H H(±)-N-[5-cyano-1-[(2-ethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-piperidin-4-ylpiperazine-1-carboxamide 27A N CHethoxy H H(+)-N-[5-cyano-1-[(2-ethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-piperidin-4-ylpiperazine-1-carboxamide 27B N CHethoxy H H(−)-N-[5-cyano-1-[(2-ethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-piperidin-4-ylpiperazine-1-carboxamide 28 N CHH H H(±)-N-[5-cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulphonyl)-2,3-dihydro-1H-indol-3-yl]-4-piperidin-4-ylpiperazine-1-carboxamide 28A N CH H H H(+)-N-[5-cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulphonyl)-2,3-dihydro-1H-indol-3-yl]-4-piperidin-4-ylpiperazine-1-carboxamide 28B N CH H H H(−)-N-[5-cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulphonyl)-2,3-dihydro-1H-indol-3-yl]-4-piperidin-4-ylpiperazine-1-carboxamide 29 N CH H methoxy H(±)-N-{5-cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulphonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl}-4-piperidin-4-ylpiperazine-1-carboxamide 29A N CHH methoxy H(+)-N-{5-cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulphonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl}-4-piperidin-4-ylpiperazine-1-carboxamide 29B N CHH methoxy H(−)-N-{5-cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulphonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl}-4-piperidin-4-ylpiperazine-1-carboxamide 30 N CHethoxy methoxy H(±)-N-[5-cyano-1-[(2-ethoxy-4-methoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-piperidin-4-ylpiperazine-1-carboxamide30A N CH ethoxy methoxy H(+)-N-[5-cyano-1-[(2-ethoxy-4-methoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-piperidin-4-ylpiperazine-1-carboxamide30B N CH ethoxy methoxy H(−)-N-[5-cyano-1-[(2-ethoxy-4-methoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-piperidin-4-ylpiperazine-1-carboxamide31 CH N methoxy methoxy methyl(±)-N-[5-cyano-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(4-methylpiperazin-1-yl)piperidine-1-carboxamide31A CH N methoxy methoxy methyl(+)-N-[5-cyano-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(4-methylpiperazin-1-yl)piperidine-1-carboxamide31B CH N methoxy methoxy methyl(−)-N-[5-cyano-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(4-methylpiperazin-1-yl)piperidine-1-carboxamide32 CH N methoxy H methyl(±)-N-{5-cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulphonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl}-4-(4-methylpiperazin-1-yl)piperidine-1-carboxamide32A CH N methoxy H methyl(+)-N-{5-cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulphonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl}-4-(4-methylpiperazin-1-yl)piperidine-1-carboxamide32B CH N methoxy H methyl(−)-N-{5-cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulphonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl}-4-(4-methylpiperazin-1-yl)piperidine-1-carboxamide33 CH N ethoxy H methyl(±)-N-[5-cyano-1-[(2-ethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(4-methylpiperazin-1-yl)piperidine-1-carboxamide33A CH N ethoxy H methyl(+)-N-[5-cyano-1-[(2-ethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(4-methylpiperazin-1-yl)piperidine-1-carboxamide33B CH N ethoxy H methyl(−)-N-[5-cyano-1-[(2-ethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(4-methylpiperazin-1-yl)piperidine-1-carboxamide34 CH N H H methyl(±)-N-[5-cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulphonyl)-2,3-dihydro-1H-indol-3-yl]-4-(4-methylpiperazin-1-yl)piperidine-1-carboxamide 34A CH NH H methyl(+)-N-[5-cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulphonyl)-2,3-dihydro-1H-indol-3-yl]-4-(4-methylpiperazin-1-yl)piperidine-1-carboxamide 34B CH NH H methyl(−)-N-[5-cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulphonyl)-2,3-dihydro-1H-indol-3-yl]-4-(4-methylpiperazin-1-yl)piperidine-1-carboxamide 35 CH N Hmethoxy methyl(±)-N-{5-cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulphonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl}-4-(4-methylpiperazin-1-yl)piperidine-1-carboxamide35A CH N H methoxy methyl(+)-N-{5-cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulphonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl}-4-(4-methylpiperazin-1-yl)piperidine-1-carboxamide35B CH N H methoxy methyl(−)-N-{5-cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulphonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl}-4-(4-methylpiperazin-1-yl)piperidine-1-carboxamide36 CH N ethoxy methoxy methyl(±)-N-[5-cyano-1-[(2-ethoxy-4-methoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(4-methylpiperazin-1-yl)piperidine-1-carboxamide36A CH N ethoxy methoxy methyl(+)-N-[5-cyano-1-[(2-ethoxy-4-methoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(4-methylpiperazin-1-yl)piperidine-1-carboxamide36B CH N ethoxy methoxy methyl(−)-N-[5-cyano-1-[(2-ethoxy-4-methoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(4-methylpiperazin-1-yl)piperidine-1-carboxamide37 CH N methoxy methoxy ethyl(±)-N-[5-cyano-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(4-ethylpiperazin-1-yl)piperidine-1-carboxamide37A CH N methoxy methoxy ethyl(+)-N-[5-cyano-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(4-ethylpiperazin-1-yl)piperidine-1-carboxamide37B CH N methoxy methoxy ethyl(−)-N-[5-cyano-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(4-ethylpiperazin-1-yl)piperidine-1-carboxamide38 CH N methoxy H ethyl(±)-N-{5-cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulphonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl}-4-(4-ethylpiperazin-1-yl)piperidine-1-carboxamide38A CH N methoxy H ethyl(+)-N-{5-cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulphonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl}-4-(4-ethylpiperazin-1-yl)piperidine-1-carboxamide38B CH N methoxy H ethyl(−)-N-{5-cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulphonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl}-4-(4-ethylpiperazin-1-yl)piperidine-1-carboxamide39 CH N ethoxy H ethyl(±)-N-[5-cyano-1-[(2-ethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(4-ethylpiperazin-1-yl)piperidine-1-carboxamide39A CH N ethoxy H ethyl(+)-N-[5-cyano-1-[(2-ethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(4-ethylpiperazin-1-yl)piperidine-1-carboxamide39B CH N ethoxy H ethyl(−)-N-[5-cyano-1-[(2-ethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(4-ethylpiperazin-1-yl)piperidine-1-carboxamide40 CH N H H ethyl(±)-N-[5-cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulphonyl)-2,3-dihydro-1H-indol-3-yl]-4-(4-ethylpiperazin-1-yl)piperidine-1-carboxamide 40A CH N HH ethyl(+)-N-[5-cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulphonyl)-2,3-dihydro-1H-indol-3-yl]-4-(4-ethylpiperazin-1-yl)piperidine-1-carboxamide 40B CH N HH ethyl(−)-N-[5-cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulphonyl)-2,3-dihydro-1H-indol-3-yl]-4-(4-ethylpiperazin-1-yl)piperidine-1-carboxamide 41 CH N Hmethoxy ethyl(±)-N-{5-cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulphonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl}-4-(4-ethylpiperazin-1-yl)piperidine-1-carboxamide41A CH N H methoxy ethyl(+)-N-{5-cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulphonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl}-4-(4-ethylpiperazin-1-yl)piperidine-1-carboxamide41B CH N H methoxy ethyl(−)-N-{5-cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulphonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl}-4-(4-ethylpiperazin-1-yl)piperidine-1-carboxamide42 CH N ethoxy methoxy ethyl(±)-N-[5-cyano-1-[(2-ethoxy-4-methoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(4-ethylpiperazin-1-yl)piperidine-1-carboxamide42A CH N ethoxy methoxy ethyl(+)-N-[5-cyano-1-[(2-ethoxy-4-methoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(4-ethylpiperazin-1-yl)piperidine-1-carboxamide42B CH N ethoxy methoxy ethyl(−)-N-[5-cyano-1-[(2-ethoxy-4-methoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(4-ethylpiperazin-1-yl)piperidine-1-carboxamide43 CH N methoxy methoxy n-(±)-N-[5-cyano-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-propyl2,3-dihydro-1H-indol-3-yl]-4-(4-propylpiperazin-1-yl)piperidine-1-carboxamide43A CH N methoxy methoxy n-(+)-N-[5-cyano-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-propyl2,3-dihydro-1H-indol-3-yl]-4-(4-propylpiperazin-1-yl)piperidine-1-carboxamide43B CH N methoxy methoxy n-(−)-N-[5-cyano-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-propyl2,3-dihydro-1H-indol-3-yl]-4-(4-propylpiperazin-1-yl)piperidine-1-carboxamide44 CH N methoxy H n-(±)-N-{5-cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulphonyl]-2-oxo-2,3-propyldihydro-1H-indol-3-yl}-4-(4-propylpiperazin-1-yl)piperidine-1-carboxamide44A CH N methoxy H n-(+)-N-{5-cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulphonyl]-2-oxo-2,3-propyldihydro-1H-indol-3-yl}-4-(4-propylpiperazin-1-yl)piperidine-1-carboxamide44B CH N methoxy H n-(−)-N-{5-cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulphonyl]-2-oxo-2,3-propyldihydro-1H-indol-3-yl}-4-(4-propylpiperazin-1-yl)piperidine-1-carboxamide45 CH N ethoxy H n-(±)-N-[5-cyano-1-[(2-ethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-propyldihydro-1H-indol-3-yl]-4-(4-propylpiperazin-1-yl)piperidine-1-carboxamide45A CH N ethoxy H n-(+)-N-[5-cyano-1-[(2-ethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-propyldihydro-1H-indol-3-yl]-4-(4-propylpiperazin-1-yl)piperidine-1-carboxamide45B CH N ethoxy H n-(−)-N-[5-cyano-1-[(2-ethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-propyldihydro-1H-indol-3-yl]-4-(4-propylpiperazin-1-yl)piperidine-1-carboxamide46 CH N H H n-(±)-N-[5-cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulphonyl)-2,3-dihydro-1H-propyl indol-3-yl]-4-(4-propylpiperazin-1-yl)piperidine-1-carboxamide46A CH N H H n-(+)-N-[5-cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulphonyl)-2,3-dihydro-1H-propyl indol-3-yl]-4-(4-propylpiperazin-1-yl)piperidine-1-carboxamide46B CH N H H n-(−)-N-[5-cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulphonyl)-2,3-dihydro-1H-propyl indol-3-yl]-4-(4-propylpiperazin-1-yl)piperidine-1-carboxamide 47CH N H methoxy n-(±)-N-{5-cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulphonyl]-2-oxo-2,3-propyldihydro-1H-indol-3-yl}-4-(4-propylpiperazin-1-yl)piperidine-1-carboxamide47A CH N H methoxy n-(+)-N-{5-cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulphonyl]-2-oxo-2,3-propyldihydro-1H-indol-3-yl}-4-(4-propylpiperazin-1-yl)piperidine-1-carboxamide47B CH N H methoxy n-(−)-N-{5-cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulphonyl]-2-oxo-2,3-propyldihydro-1H-indol-3-yl}-4-(4-propylpiperazin-1-yl)piperidine-1-carboxamide48 CH N ethoxy methoxy n-(±)-N-[5-cyano-1-[(2-ethoxy-4-methoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-propyl2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(4-propylpiperazin-1-yl)piperidine-1-carboxamide48A CH N ethoxy methoxy n-(+)-N-[5-cyano-1-[(2-ethoxy-4-methoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-propyl2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(4-propylpiperazin-1-yl)piperidine-1-carboxamide48B CH N ethoxy methoxy n-(−)-N-[5-cyano-1-[(2-ethoxy-4-methoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-propyloxo-2,3-dihydro-1H-indol-3-yl]-4-(4-propylpiperazin-1-yl)piperidine-1-carboxamide49 CH N methoxy methoxy isopropyl(±)-N-[5-cyano-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(4-isopropylpiperazin-1-yl)piperidine-1-carboxamide49A CH N methoxy methoxy isopropyl(+)-N-[5-cyano-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(4-isopropylpiperazin-1-yl)piperidine-1-carboxamide49B CH N methoxy methoxy isopropyl(−)-N-[5-cyano-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(4-isopropylpiperazin-1-yl)piperidine-1-carboxamide50 CH N methoxy H isopropyl(±)-N-{5-cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulphonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl}-4-(4-isopropylpiperazin-1-yl)piperidine-1-carboxamide50A CH N methoxy H isopropyl(+)-N-{5-cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulphonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl}-4-(4-isopropylpiperazin-1-yl)piperidine-1-carboxamide50B CH N methoxy H isopropyl(−)-N-{5-cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulphonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl}-4-(4-isopropylpiperazin-1-yl)piperidine-1-carboxamide51 CH N ethoxy H isopropyl(±)-N-[5-cyano-1-[(2-ethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(4-isopropylpiperazin-1-yl)piperidine-1-carboxamide51A CH N ethoxy H isopropyl(+)-N-[5-cyano-1-[(2-ethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(4-isopropylpiperazin-1-yl)piperidine-1-carboxamide51B CH N ethoxy H isopropyl(−)-N-[5-cyano-1-[(2-ethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(4-isopropylpiperazin-1-yl)piperidine-1-carboxamide52 CH N H H isopropyl(±)-N-[5-cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulphonyl)-2,3-dihydro-1H-indol-3-yl]-4-(4-isopropylpiperazin-1-yl)piperidine-1-carboxamide 52A CHN H H isopropyl(+)-N-[5-cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulphonyl)-2,3-dihydro-1H-indol-3-yl]-4-(4-isopropylpiperazin-1-yl)piperidine-1-carboxamide 52B CHN H H isopropyl(−)-N-[5-cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulphonyl)-2,3-dihydro-1H-indol-3-yl]-4-(4-isopropylpiperazin-1-yl)piperidine-1-carboxamide 53 CHN H methoxy isopropyl(±)-N-{5-cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulphonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl}-4-(4-isopropylpiperazin-1-yl)piperidine-1-carboxamide53A CH N H methoxy isopropyl(+)-N-{5-cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulphonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl}-4-(4-isopropylpiperazin-1-yl)piperidine-1-carboxamide53B CH N H methoxy isopropyl(−)-N-{5-cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulphonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl}-4-(4-isopropylpiperazin-1-yl)piperidine-1-carboxamide54 CH N ethoxy methoxy isopropyl(±)-N-[5-cyano-1-[(2-ethoxy-4-methoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(4-isopropylpiperazin-1-yl)piperidine-1-carboxamide54A CH N ethoxy methoxy isopropyl(+)-N-[5-cyano-1-[(2-ethoxy-4-methoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(4-isopropylpiperazin-1-yl)piperidine-1-carboxamide54B CH N ethoxy methoxy isopropyl(−)-N-[5-cyano-1-[(2-ethoxy-4-methoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(4-isopropylpiperazin-1-yl)piperidine-1-carboxamide55 CH N methoxy methoxy H(±)-N-[5-cyano-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-piperazin-1-ylpiperidine-1-carboxamide 55ACH N methoxy methoxy H(+)-N-[5-cyano-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-piperazin-1-ylpiperidine-1-carboxamide 55BCH N methoxy methoxy H(−)-N-[5-cyano-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-piperazin-1-ylpiperidine-1-carboxamide 56CH N methoxy H H(±)-N-{5-cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulphonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl}-4-piperazin-1-ylpiperidine-1-carboxamide 56A CH Nmethoxy H H(+)-N-{5-cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulphonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl}-4-piperazin-1-ylpiperidine-1-carboxamide 56B CH Nmethoxy H H(−)-N-{5-cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulphonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl}-4-piperazin-1-ylpiperidine-1-carboxamide 57 CH Nethoxy H H(±)-N-[5-cyano-1-[(2-ethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-piperazin-1-ylpiperidine-1-carboxamide 57A CH Nethoxy H H(+)-N-[5-cyano-1-[(2-ethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-piperazin-1-ylpiperidine-1-carboxamide 57B CH Nethoxy H H(−)-N-[5-cyano-1-[(2-ethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-piperazin-1-ylpiperidine-1-carboxamide 58 CH NH H H(±)-N-[5-cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulphonyl)-2,3-dihydro-1H-indol-3-yl]-4-piperazin-1-ylpiperidine-1-carboxamide 58A CH N H H H(+)-N-[5-cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulphonyl)-2,3-dihydro-1H-indol-3-yl]-4-piperazin-1-ylpiperidine-1-carboxamide 58B CH N H H H(−)-N-[5-cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulphonyl)-2,3-dihydro-1H-indol-3-yl]-4-piperazin-1-ylpiperidine-1-carboxamide 59 CH N H methoxy H(±)-N-{5-cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulphonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl}-4-piperazin-1-ylpiperidine-1-carboxamide 59A CH NH methoxy H(+)-N-{5-cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulphonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl}-4-piperazin-1-ylpiperidine-1-carboxamide 59B CH NH methoxy H(−)-N-{5-cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulphonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl}-4-piperazin-1-ylpiperidine-1-carboxamide 60 CH Nethoxy methoxy H(±)-N-[5-cyano-1-[(2-ethoxy-4-methoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-piperazin-1-ylpiperidine-1-carboxamide60A CH N ethoxy methoxy H(+)-N-[5-cyano-1-[(2-ethoxy-4-methoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-piperazin-1-ylpiperidine-1-carboxamide60B CH N ethoxy methoxy H(−)-N-[5-cyano-1-[(2-ethoxy-4-methoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-piperazin-1-ylpiperidine-1-carboxamide61 CH CH methoxy methoxy methyl(±)-N-[5-cyano-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-1′-methyl-4,4′-bipiperidine-1-carboxamide 61ACH CH methoxy methoxy methyl(+)-N-[5-cyano-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-1′-methyl-4,4′-bipiperidine-1-carboxamide 61BCH CH methoxy methoxy methyl(−)-N-[5-cyano-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-1′-methyl-4,4′-bipiperidine-1-carboxamide 62CH CH methoxy H methyl(±)-N-{5-cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulphonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl}-1′-methyl-4,4′-bipiperidine-1-carboxamide 62A CHCH methoxy H methyl(+)-N-{5-cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulphonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl}-1′-methyl-4,4′-bipiperidine-1-carboxamide 62B CHCH methoxy H methyl(−)-N-{5-cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulphonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl}-1′-methyl-4,4′-bipiperidine-1-carboxamide 63 CHCH ethoxy H methyl(±)-N-[5-cyano-1-[(2-ethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-1′-methyl-4,4′-bipiperidine-1-carboxamide 63A CHCH ethoxy H methyl(+)-N-[5-cyano-1-[(2-ethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-1′-methyl-4,4′-bipiperidine-1-carboxamide 63B CHCH ethoxy H methyl(−)-N-[5-cyano-1-[(2-ethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-1′-methyl-4,4′-bipiperidine-1-carboxamide 64 CHCH H H methyl(±)-N-[5-cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulphonyl)-2,3-dihydro-1H-indol-3-yl]-1′-methyl-4,4′-bipiperidine-1-carboxamide 64A CH CH H Hmethyl(+)-N-[5-cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulphonyl)-2,3-dihydro-1H-indol-3-yl]-1′-methyl-4,4′-bipiperidine-1-carboxamide 64B CH CH H Hmethyl(−)-N-[5-cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulphonyl)-2,3-dihydro-1H-indol-3-yl]-1′-methyl-4,4′-bipiperidine-1-carboxamide 65 CH CH H methoxymethyl(±)-N-{5-cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulphonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl}-1′-methyl-4,4′-bipiperidine-1-carboxamide 65A CHCH H methoxy methyl(+)-N-{5-cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulphonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl}-1′-methyl-4,4′-bipiperidine-1-carboxamide 65B CHCH H methoxy methyl(−)-N-{5-cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulphonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl}-1′-methyl-4,4′-bipiperidine-1-carboxamide 66 CHCH ethoxy methoxy methyl(±)-N-[5-cyano-1-[(2-ethoxy-4-methoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-1′-methyl-4,4′-bipiperidine-1-carboxamide66A CH CH ethoxy methoxy methyl(+)-N-[5-cyano-1-[(2-ethoxy-4-methoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-1′-methyl-4,4′-bipiperidine-1-carboxamide66B CH CH ethoxy methoxy methyl(−)-N-[5-cyano-1-[(2-ethoxy-4-methoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-1′-methyl-4,4′-bipiperidine-1-carboxamide67 CH CH methoxy methoxy ethyl(±)-N-[5-cyano-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-1′-ethyl-4,4′-bipiperidine-1-carboxamide 67ACH CH methoxy methoxy ethyl(+)-N-[5-cyano-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-1′-ethyl-4,4′-bipiperidine-1-carboxamide 67BCH CH methoxy methoxy ethyl(−)-N-[5-cyano-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-1′-ethyl-4,4′-bipiperidine-1-carboxamide 68CH CH methoxy H ethyl(±)-N-{5-cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulphonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl}-1′-ethyl-4,4′-bipiperidine-1-carboxamide 68A CHCH methoxy H ethyl(+)-N-{5-cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulphonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl}-1′-ethyl-4,4′-bipiperidine-1-carboxamide 68B CHCH methoxy H ethyl(−)-N-{5-cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulphonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl}-1′-ethyl-4,4′-bipiperidine-1-carboxamide 69 CH CHethoxy H ethyl(±)-N-[5-cyano-1-[(2-ethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-1′-ethyl-4,4′-bipiperidine-1-carboxamide 69A CHCH ethoxy H ethyl(+)-N-[5-cyano-1-[(2-ethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-1′-ethyl-4,4′-bipiperidine-1-carboxamide 69B CHCH ethoxy H ethyl(−)-N-[5-cyano-1-[(2-ethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-1′-ethyl-4,4′-bipiperidine-1-carboxamide 70 CH CHH H ethyl(±)-N-[5-cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulphonyl)-2,3-dihydro-1H-indol-3-yl]-1′-ethyl-4,4′-bipiperidine-1-carboxamide 70A CH CH H H ethyl(+)-N-[5-cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulphonyl)-2,3-dihydro-1H-indol-3-yl]-1′-ethyl-4,4′-bipiperidine-1-carboxamide 70B CH CH H H ethyl(−)-N-[5-cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulphonyl)-2,3-dihydro-1H-indol-3-yl]-1′-ethyl-4,4′-bipiperidine-1-carboxamide 71 CH CH H methoxyethyl(±)-N-{5-cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulphonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl}-1′-ethyl-4,4′-bipiperidine-1-carboxamide 71A CHCH H methoxy ethyl(+)-N-{5-cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulphonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl}-1′-ethyl-4,4′-bipiperidine-1-carboxamide 71B CHCH H methoxy ethyl(−)-N-{5-cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulphonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl}-1′-ethyl-4,4′-bipiperidine-1-carboxamide 72 CH CHethoxy methoxy ethyl(±)-N-[5-cyano-1-[(2-ethoxy-4-methoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-1′-ethyl-4,4′-bipiperidine-1-carboxamide72A CH CH ethoxy methoxy ethyl(+)-N-[5-cyano-1-[(2-ethoxy-4-methoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-1′-ethyl-4,4′-bipiperidine-1-carboxamide72B CH CH ethoxy methoxy ethyl(−)-N-[5-cyano-1-[(2-ethoxy-4-methoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-1′-ethyl-4,4′-bipiperidine-1-carboxamide73 CH CH methoxy methoxy n-(±)-N-[5-cyano-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-propyl2,3-dihydro-1H-indol-3-yl]-1′-propyl-4,4′-bipiperidine-1-carboxamide 73ACH CH methoxy methoxy n-(+)-N-[5-cyano-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-propyl2,3-dihydro-1H-indol-3-yl]-1′-propyl-4,4′-bipiperidine-1-carboxamide 73BCH CH methoxy methoxy n-(−)-N-[5-cyano-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-propyl2,3-dihydro-1H-indol-3-yl]-1′-propyl-4,4′-bipiperidine-1-carboxamide 74CH CH methoxy H n-(±)-N-{5-cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulphonyl]-2-oxo-2,3-propyl dihydro-1H-indol-3-yl}-1′-propyl-4,4′-bipiperidine-1-carboxamide74A CH CH methoxy H n-(+)-N-{5-cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulphonyl]-2-oxo-2,3-propyl dihydro-1H-indol-3-yl}-1′-propyl-4,4′-bipiperidine-1-carboxamide74B CH CH methoxy H n-(−)-N-{5-cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulphonyl]-2-oxo-2,3-propyl dihydro-1H-indol-3-yl}-1′-propyl-4,4′-bipiperidine-1-carboxamide75 CH CH ethoxy H n-(±)-N-[5-cyano-1-[(2-ethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-propyl dihydro-1H-indol-3-yl]-1′-propyl-4,4′-bipiperidine-1-carboxamide75A CH CH ethoxy H n-(+)-N-[5-cyano-1-[(2-ethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-propyl dihydro-1H-indol-3-yl]-1′-propyl-4,4′-bipiperidine-1-carboxamide75B CH CH ethoxy H n-(−)-N-[5-cyano-1-[(2-ethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-propyl dihydro-1H-indol-3-yl]-1′-propyl-4,4′-bipiperidine-1-carboxamide76 CH CH H H n-(±)-N-[5-cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulphonyl)-2,3-dihydro-1H-propyl indol-3-yl]-1′-propyl-4,4′-bipiperidine-1-carboxamide 76A CH CH HH n-(+)-N-[5-cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulphonyl)-2,3-dihydro-1H-propyl indol-3-yl]-1′-propyl-4,4′-bipiperidine-1-carboxamide 76B CH CH HH n-(−)-N-[5-cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulphonyl)-2,3-dihydro-1H-propyl indol-3-yl]-1′-propyl-4,4′-bipiperidine-1-carboxamide 77 CH CH Hmethoxy n-(±)-N-{5-cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulphonyl]-2-oxo-2,3-propyl dihydro-1H-indol-3-yl}-1′-propyl-4,4′-bipiperidine-1-carboxamide77A CH CH H methoxy n-(+)-N-{5-cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulphonyl]-2-oxo-2,3-propyl dihydro-1H-indol-3-yl}-1′-propyl-4,4′-bipiperidine-1-carboxamide77B CH CH H methoxy n-(−)-N-{5-cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulphonyl]-2-oxo-2,3-propyl dihydro-1H-indol-3-yl}-1′-propyl-4,4′-bipiperidine-1-carboxamide78 CH CH ethoxy methoxy n-(±)-N-[5-cyano-1-[(2-ethoxy-4-methoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-propyl2-oxo-2,3-dihydro-1H-indol-3-yl]-1′-propyl-4,4′-bipiperidine-1-carboxamide78A CH CH ethoxy methoxy n-(+)-N-[5-cyano-1-[(2-ethoxy-4-methoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-propyl2-oxo-2,3-dihydro-1H-indol-3-yl]-1′-propyl-4,4′-bipiperidine-1-carboxamide78B CH CH ethoxy methoxy n-(−)-N-[5-cyano-1-[(2-ethoxy-4-methoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-propyloxo-2,3-dihydro-1H-indol-3-yl]-1′-propyl-4,4′-bipiperidine-1-carboxamide79 CH CH methoxy methoxy isopropyl(±)-N-[5-cyano-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-1′-isopropyl-4,4′-bipiperidine-1-carboxamide79A CH CH methoxy methoxy isopropyl(+)-N-[5-cyano-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-1′-isopropyl-4,4′-bipiperidine-1-carboxamide79B CH CH methoxy methoxy isopropyl(−)-N-[5-cyano-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-1′-isopropyl-4,4′-bipiperidine-1-carboxamide80 CH CH methoxy H isopropyl(±)-N-{5-cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulphonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl}-1′-isopropyl-4,4′-bipiperidine-1-carboxamide 80ACH CH methoxy H isopropyl(+)-N-{5-cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulphonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl}-1′-isopropyl-4,4′-bipiperidine-1-carboxamide 80BCH CH methoxy H isopropyl(−)-N-{5-cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulphonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl}-1′-isopropyl-4,4′-bipiperidine-1-carboxamide 81CH CH ethoxy H isopropyl(±)-N-[5-cyano-1-[(2-ethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-1′-isopropyl-4,4′-bipiperidine-1-carboxamide 81ACH CH ethoxy H isopropyl(+)-N-[5-cyano-1-[(2-ethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-1′-isopropyl-4,4′-bipiperidine-1-carboxamide 81BCH CH ethoxy H isopropyl(−)-N-[5-cyano-1-[(2-ethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-1′-isopropyl-4,4′-bipiperidine-1-carboxamide 82CH CH H H isopropyl(±)-N-[5-cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulphonyl)-2,3-dihydro-1H-indol-3-yl]-1′-isopropyl-4,4′-bipiperidine-1-carboxamide 82A CH CH H Hisopropyl(+)-N-[5-cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulphonyl)-2,3-dihydro-1H-indol-3-yl]-1′-isopropyl-4,4′-bipiperidine-1-carboxamide 82B CH CH H Hisopropyl(−)-N-[5-cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulphonyl)-2,3-dihydro-1H-indol-3-yl]-1′-isopropyl-4,4′-bipiperidine-1-carboxamide 83 CH CH Hmethoxy isopropyl(±)-N-{5-cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulphonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl}-1′-isopropyl-4,4′-bipiperidine-1-carboxamide 83ACH CH H methoxy isopropyl(+)-N-{5-cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulphonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl}-1′-isopropyl-4,4′-bipiperidine-1-carboxamide 83BCH CH H methoxy isopropyl(−)-N-{5-cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulphonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl}-1′-isopropyl-4,4′-bipiperidine-1-carboxamide 84CH CH ethoxy methoxy isopropyl(±)-N-[5-cyano-1-[(2-ethoxy-4-methoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-1′-isopropyl-4,4′-bipiperidine-1-carboxamide84A CH CH ethoxy methoxy isopropyl(+)-N-[5-cyano-1-[(2-ethoxy-4-methoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-1′-isopropyl-4,4′-bipiperidine-1-carboxamide84B CH CH ethoxy methoxy isopropyl(−)-N-[5-cyano-1-[(2-ethoxy-4-methoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-1′-isopropyl-4,4′-bipiperidine-1-carboxamide85 CH CH methoxy methoxy H(±)-N-[5-cyano-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4,4′-bipiperidine-1-carboxamide 85A CH CHmethoxy methoxy H(+)-N-[5-cyano-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4,4′-bipiperidine-1-carboxamide 85B CH CHmethoxy methoxy H(−)-N-[5-cyano-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4,4′-bipiperidine-1-carboxamide 86 CH CHmethoxy H H(±)-N-{5-cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulphonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl}-4,4′-bipiperidine-1-carboxamide 86A CH CH methoxyH H(+)-N-{5-cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulphonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl}-4,4′-bipiperidine-1-carboxamide 86B CH CH methoxyH H(−)-N-{5-cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulphonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl}-4,4′-bipiperidine-1-carboxamide 87 CH CH ethoxy HH(±)-N-[5-cyano-1-[(2-ethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4,4′-bipiperidine-1-carboxamide 87A CH CH ethoxyH H(+)-N-[5-cyano-1-[(2-ethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4,4′-bipiperidine-1-carboxamide 87B CH CH ethoxyH H(−)-N-[5-cyano-1-[(2-ethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4,4′-bipiperidine-1-carboxamide 88 CH CH H H H(±)-N-[5-cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulphonyl)-2,3-dihydro-1H-indol-3-yl]-4,4′-bipiperidine-1-carboxamide 88A CH CH H H H(+)-N-[5-cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulphonyl)-2,3-dihydro-1H-indol-3-yl]-4,4′-bipiperidine-1-carboxamide 88B CH CH H H H(−)-N-[5-cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulphonyl)-2,3-dihydro-1H-indol-3-yl]-4,4′-bipiperidine-1-carboxamide 89 CH CH H methoxy H(±)-N-{5-cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulphonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl}-4,4′-bipiperidine-1-carboxamide 89A CH CH Hmethoxy H(+)-N-{5-cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulphonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl}-4,4′-bipiperidine-1-carboxamide 89B CH CH Hmethoxy H(−)-N-{5-cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulphonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl}-4,4′-bipiperidine-1-carboxamide 90 CH CH ethoxymethoxy H(±)-N-[5-cyano-1-[(2-ethoxy-4-methoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4,4′-bipiperidine-1-carboxamide 90A CHCH ethoxy methoxy H(+)-N-[5-cyano-1-[(2-ethoxy-4-methoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4,4′-bipiperidine-1-carboxamide 90B CHCH ethoxy methoxy H(−)-N-[5-cyano-1-[(2-ethoxy-4-methoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4,4′-bipiperidine-1-carboxamide

Methods for Determining the Biological Activity Vasopressin V1b ReceptorBinding Assay: Substances:

The test substances were dissolved in a concentration of 10⁻² M in DMSOand further diluted to 5×10⁻⁴ M to 5×10⁻⁹ M in DMSO. This series of DMSOpredilutions was diluted 1:10 with assay buffer. The substanceconcentration was again diluted 1:5 in the assay mixture (2% DMSO in themixture).

Membrane Preparation:

CHO-K1 cells with stably expressed human vasopressin V1b receptor (clone3H2) were harvested and homogenized in 50 mM Tris-HCl and in thepresence of protease inhibitors (Roche complete Mini #1836170) with aPolytron homogenizer at a medium setting for 2×10 seconds andsubsequently centrifuged at 40 000×g for 1 h. The membrane pellet wasagain homogenized and centrifuged as described and then taken up in 50mM Tris-HCl, pH 7.4, homogenized and stored in aliquots frozen in liquidnitrogen at −190° C.

Binding Assay:

The binding assay was carried out by a method based on that of Tahara etal. (Tahara A et al., Brit. J. Pharmacol. 125, 1463-1470 (1998)). Theincubation buffer was: 50 mM Tris, 10 mM MgCl₂, 0.1% BSA, pH 7.4.

In the assay mixture (250 μl), membranes (50 μg/ml protein in incubationbuffer) from CHO-K1 cells with stably expressed human V1b receptors(cell line hV1b_(—)3H2_CHO) were incubated with 1.5 nM ³H-AVP(8-Arg-vasopressin, PerkinElmer #18479) in incubation buffer (50 mMTris, 10 mM MgCl₂, 0.1% BSA, pH 7.4) (total binding) or additionallywith increasing concentrations of test substance (displacementexperiment). The nonspecific binding was determined with 1 μM AVP(Bachem # H1780). All determinations were carried out as triplicatedeterminations. After incubation (60 minutes at room temperature), thefree radioligand was removed by vacuum filtration (Skatron cellharvester 7000) through Wathman GF/B glass fibre filter mats, and thefilters were transferred into scintillation vials. The liquidscintillation measurement took place in a Tricarb model 2000 or 2200CAinstrument (Packard). Conversion of the measured cpm into dpm wascarried out with the aid of a standard quench series.

Evaluation:

The binding parameters were calculated by nonlinear regression in SAS.The algorithms of the program operate in analogy to the LIGAND analysisprogram (Munson PJ and Rodbard D, Analytical Biochem. 107, 220-239(1980)). The Kd of ³H-AVP for the recombinant human V1b receptors is 0.4nM and was used to determine the Ki value.

The test reveals that compounds of the present invention generally havehigh affinities towards the V1b receptor which, expressed asK_(i)(h-V1b) values, are generally below 150 nM, in particular at most50 nM and especially at most 10 nM. The results are given in table 3

Vasopressin V1a Receptor Binding Assay: Substances:

The test substances were dissolved in a concentration of 10⁻² M in DMSO.These DMSO solutions were further diluted in incubation buffer (50 mMTris, 10 mM MgCl₂, 0.1% BSA, pH 7.4).

Membrane Preparation:

CHO-K1 cells with stably expressed human vasopressin V1a receptor (clone5) were harvested and homogenized in 50 mM Tris-HCl and in the presenceof protease inhibitors (Roche complete Mini #1836170) with a Polytronhomogenizer at a medium setting for 2×10 seconds and subsequentlycentrifuged at 40 000×g for 1 h. The membrane pellet was againhomogenized and centrifuged as described and then taken up in 50 mMTris-HCl, pH 7.4, homogenized and stored in aliquots frozen in liquidnitrogen at −190° C.

Binding Assay:

The binding assay was carried out by a method based on that of Tahara etal. (Tahara A et al., Brit. J. Pharmacol. 125, 1463-1470 (1998)).

The incubation buffer was: 50 mM Tris, 10 mM MgCl₂, 0.1% BSA, pH 7.4.

In the assay mixture (250 μl), membranes (20 μg/ml protein in incubationbuffer) from CHO-K1 cells with stably expressed human V1a receptors(cell line hV1a_(—)5_CHO) were incubated with 0.04 nM ¹²⁵I-AVP(8-Arg-vasopressin, NEX 128) in incubation buffer (50 mM Tris, 10 mMMgCl₂, 0.1% BSA, pH 7.4) (total binding) or additionally with increasingconcentrations of test substance (displacement experiment). Thenonspecific binding was determined with 1 μM AVP (Bachem # H1780).Triplicate determinations were carried out.

After incubation (60 minutes at room temperature), the free radioligandwas removed by vacuum filtration (Skatron cell harvester 7000) throughWathman GF/B glass fibre filter mats, and the filters were transferredinto scintillation vials.

The liquid scintillation measurement took place in a Tricarb model 2000or 2200CA instrument (Packard). Conversion of the measured cpm into dpmwas carried out with the aid of a standard quench series.

Evaluation:

The binding parameters were calculated by nonlinear regression in SAS.The algorithms of the program operate in analogy to the LIGAND analysisprogram (Munson PJ and Rodbard D, Analytical Biochem. 107, 220-239(1980)). The Kd of ¹²⁵I-AVP for the recombinant hV1a receptors wasdetermined in saturation experiments. A Kd of 1.33 nM was used todetermine the Ki value.

The test reveals that compounds of the present invention generally haveselectivity towards the V1b receptor in comparison with V1a receptor,which, expressed as K_(i)(h-V1a)/K_(i)(h-V1b) values generally exceed 10and are frequently at least 15, in particular at least 50 and especiallyat least 100. The results are given in table 3.

Vasopressin V2 Receptor Binding Assay: Substances:

The test substances were dissolved in a concentration of 10⁻² M in DMSO.This DMSO solution was further diluted in incubation buffer (50 mM Tris,10 mM MgCl₂, 0.1% BSA, pH 7.4).

Membrane Preparation:

CHO-K1 cells with stably expressed human vasopressin V2 receptor (clone23) were harvested and homogenized in 50 mM Tris-HCl and in the presenceof protease inhibitors (Roche complete Mini #1836170) with a Polytronhomogenizer at a medium setting for 2×10 seconds and subsequentlycentrifuged at 40 000×g for 1 h. The membrane pellet was againhomogenized and centrifuged as described and then taken up in 50 mMTris-HCl, pH 7.4, homogenized and stored in aliquots frozen in liquidnitrogen at −190° C.

Binding Assay:

The binding assay was carried out by a method based on that of Tahara etal. (Tahara A et al., Brit. J. Pharmacol. 125, 1463-1470 (1998)).

The incubation buffer was: 50 mM Tris, 10 mM MgCl₂, 0.1% BSA, pH 7.4.

In the assay mixture (250 μl), membranes (50 μg/ml protein in incubationbuffer) from CHO-K1 cells with stably expressed human V2 receptors (cellline hV2_(—)23_CHO) were incubated with 1-2 nM ³H-AVP(8-Arg-vasopressin, PerkinElmer #18479) in incubation buffer (50 mMTris, 10 mM MgCl₂, 0.1% BSA, pH 7.4) (total binding) or additionallywith increasing concentrations of test substance (displacementexperiment). The nonspecific binding was determined with 1 μM AVP(Bachem # H1780). Triplicate determinations were carried out.

After incubation (60 minutes at room temperature), the free radioligandwas removed by vacuum filtration (Skatron cell harvester 7000) throughWathman GF/B glass fibre filter mats, and the filters were transferredinto scintillation vials.

The liquid scintillation measurement took place in a Tricarb model 2000or 2200CA instrument (Packard). Conversion of the measured cpm into dpmwas carried out with the aid of a standard quench series.

Evaluation:

The binding parameters were calculated by nonlinear regression in SAS.The algorithms of the program operate in analogy to the LIGAND analysisprogram (Munson PJ and Rodbard D, Analytical Biochem. 107, 220-239(1980)). The Kd of ³H-AVP for the recombinant hV2 receptors is 2.4 nMand was used to determine the Ki value.

The test reveals that compounds of the present invention generally haveselectivity towards the V1b receptor in comparison with V2 receptor,which, expressed as K_(i)(h-V2)/K_(i)(h-V1b) values generally exceed 10and are frequently at least 15, in particular at least 25 and especiallyat least 50.

Oxytocin Receptor Binding Assay Substances:

The substances were dissolved in a concentration of 10⁻² M in DMSO anddiluted with incubation buffer (50 mM Tris, 10 mM MgCl₂, 0.1% BSA, pH7.4).

Cell Preparation:

Confluent HEK-293 cells with transiently expressing recombinant humanoxytocin receptors were centrifuged at 750×g and at room temperature for5 minutes. The residue was taken up in ice-cold lysis buffer (50 mMTris-HCl, 10% glycerol, pH 7.4 and Roche Complete Protease Inhibitor)and subjected to an osmotic shock at 4° C. for 20 minutes. The lyzedcells were then centrifuged at 750×g and at 4° C. for 20 minutes, theresidue was taken up in incubation buffer, and aliquots of 10⁷ cells/mlwere prepared. The aliquots were frozen at −80° C. until used.

Binding Assay:

On the day of the experiment, the cells were thawed, diluted withincubation buffer and homogenized using a Multipette Combitip(Eppendorf, Hamburg). The reaction mixture of 0.250 ml was composed of 2to 5×10⁴ recombinant cells, 3-4 nM ³H-oxytocin (PerkinElmer, NET 858) inthe presence of test substance (inhibition plot) or only incubationbuffer (total binding). The nonspecific binding was determined with 10⁻⁶M oxytocin (Bachem AG, H2510). Determinations in triplicate were set up.Bound and free radioligand were separated by filtration under vacuumwith Whatman GF/B glass fibre filters using a Skatron cell harvester7000. The bound radioactivity was determined by liquid scintillationmeasurement in a Tricarb beta counter, model 2000 or 2200CA (Packard).

Evaluation:

The binding parameters were calculated by nonlinear regression analysis(SAS), in analogy to the LIGAND program of Munson and Rodbard(Analytical Biochem 1980; 107: 220-239). The Kd of ³H-oxytocin for therecombinant hOT receptors is 7.6 nM and was used to determine the Kivalue.

The test reveals that compounds of the present invention generally haveselectivity towards the V1b receptor in comparison with Oxytocinreceptor, which, expressed as K_(i)(h-OT)/K_(i)(h-V1b) values generallyexceed 10 and are frequently at least 15, in particular at least 25 andespecially at least 50. The results are given in table 3.

TABLE 3 K_(i)(h-V1b)* Example [nM] K_(i)(h-V1a)/K_(i)(h-V1b)*K_(i)(h-OT)/K_(i)(h-V1b)*  1 +++ +++ +++  1B +++ +++ +++  2 ++ +++ +++ 3 ++ +++ +++  4 ++ ++ ++  7B +++ +++ +++ 25 +++ +++ ++ 31 +++ +++ +++31B +++ +++ +++ 32 ++ + +++ 35 +++ + ++ 37 +++ +++ +++ 37B +++ +++ +++40 +++ ++ +++ 40B +++ + +++ 43 +++ +++ +++ 55 +++ +++ ++ 61 +++ +++ +++61B +++ +++ +++ 67 +++ +++ +++ 67B +++ +++ +++ 85 +++ +++ ++K_(i)(h-V1b) K_(i)(h-V1a)/K_(i)(h-V1b)K_(i)(h-OT)/K_(i)(h-V1b) + >50-150 nM 15-50 15-25 ++ 10-50nM >50-100 >25-50  +++ <10 nM >100 >50

Determination of the Microsomal Half-Life:

The metabolic stability of the compounds of the invention was determinedin the following assay.

The test substances are incubated in a concentration of 0.5 μM asfollows:

0.5 μM test substance is preincubated together with liver microsomes ofvarious species (rat, human or other species) (0.25 mg of microsomalprotein/ml) in 0.05M potassium phosphate buffer pH 7.4 in microtitreplates at 37° C. for 5 min. The reaction is started by adding NADPH (1mg/ml). 50 μl aliquots are taken after 0, 5, 10, 15, 20 and 30 min, andthe reaction is stopped immediately with the same volume of acetonitrileand cooled down. The samples are frozen until analyzed. Using MSMS, theremaining concentration of undegraded test substance is determined. Fromthe increase of the test substance signal/time unit curve, the half-life(T1/2) is determined, where the half-life of the test substance can becalculated, assuming first order kinetics, from the decrease in theconcentration of the compound with time. The microsomal clearance (mCi)is calculated as mCl=In2/T1/2/(content of microsomal protein inmg/ml)×1000 [ml/min/mg] (modified according to the literaturereferences: Di, The Society for Biomoleculaur Screening, 2003, 453-462;Obach, DMD, 1999 vol 27. N 11, 1350-1359).

The test reveals that compounds of the present invention generally havea high metabolic stability, which result in human microsomal clearancevalues of generally at most 220 μl min⁻¹ mg⁻¹, frequently 120 μl min⁻¹mg⁻¹ and in particular at most 60 μl min⁻¹ mg⁻¹. The results are givenin table 4.

TABLE 4 Human Mikrosomal Clearance Example [μl min⁻¹ mg⁻¹]  1 +++  1B+++  4 +++  5 +++  7B +++ 25 +++ 31 ++ 31B +++ 34 +++ 35 ++ 37 ++ 37B+++ 40 ++ 40B ++ 55 ++ 61B +++ 85 ++ Human MikrosomalClearance + >120-220 μl min⁻¹ mg⁻¹ ++ 60-120 μl min⁻¹ mg⁻¹ +++ <60 μlmin⁻¹ mg⁻¹

Determination of Plasma Protein Binding (PPB) by Equilibrium Dialysis:

150 μl of rat or human plasma, with 1 or 10 μM of test substance added,is pipetted onto one side of the 96-well dialysis chambers, 150 μl ofPPS buffer are pipetted onto the other side. The chambers are separatedby a dialysis membrane having a cut-off of 6-8000 dalton.

The 96-well dialysis chambers are covered and gently shaken overnight.

The next morning, 10 μl of plasma are removed and diluted with 90 μl ofPPS buffer, and the protein is precipitated using 200 μl ofacetonitrile. The precipitated protein is removed by centrifugation, and100 μl of the supernatant are used for MSMS analysis. From the bufferside, 100 μl are removed for MSMS analysis. See also the followingliterature reference: Banker, Journal of Pharmaceutical Sciences Vol.92, 5, 967-974, 2003.

Methods for the In Vitro Determination of Cytochrom P450 (CYP)Inhibition Luminescence Substrates for 2C9 and 3A4:

0.4 mg/ml of human liver microsomes are preincubated for 10 minutes withthe test substances to be tested (0-20 μM), the CYP specific substrates,in 0.05 M potassium phosphate buffer pH 7.4 at 37° C. The Cyp-specificsubstrate for CYP 2C9 is luciferin H, that for CYP 3A4 is luciferin BE.The reaction is started by addition of NADPH. After 30 min of incubationat RT, the luciferin detection reagent is added, and the resultingluminescence signal is measured (modified according to literaturereference: Promega, Technical Bulletin P450-GLO™ Assays).

Midazolam CYP 3A4 Time-Dependent Inhibition

The test consists of 2 parts. In the first part, the test substance ispreincubated with the liver microsomes (with NADPH)=preincubation,followed by addition of the substrate; in the second part, substrate andtest substance are added simultaneously=coincubation.

Preincubation:

0.05 mg/ml of microsomal protein (human liver microsomes) arepreincubated with 0-10 μM (or 50 μM) of test substance in 50 mMpotassium phosphate buffer for 5 min. The reaction is started usingNADPH. After 30 min, 4 μM of midazolam (final concentration) are added,and the mixture is incubated for a further 10 min. After 10 min, 75 μlof the reaction solution are removed and quenched with 150 μl ofacetonitrile solution.

Coincubation:

0.05 mg/ml of microsomal protein (human liver microsomes), 4 μMmidazolam (final concentration) and 0-10 μM (or 50 μM) of test substanceare preincubated in 50 mM potassium phosphate buffer for 5 min. Thereaction is started using NADPH. After 10 min, 75 μl of the reactionsolution are removed and quenched with 150 μl of acetonitrile solution.The samples are frozen until analyzed by MSMS (modified according toliterature references:

-   Obdach, Journal of Pharmacology & Experimental Therapeutics, Vol    316, 1, 336-348, 2006; Walsky, Drug Metabolism and Disposition Vol    32, 6, 647-660, 2004).    Method for Determining the Solubility in Water (in mg/ml)

The solubility in water of the compounds according to the invention canbe determined, for example, according to the so-called “shake flask”method (according to ASTM International: E 1148-02, Standard testmethods for measurement of aqueous solubility, Book of Standards Volume11.05.). Here, an excess of the solid compound is added to a buffersolution having a certain pH (for example phosphate buffer pH 7.4) andthe resulting mixture is shaken or stirred until the steady state hasbeen reached (typically 24 or 48 hours, sometimes even up to 7 days).The undissolved solid is then removed by filtration or centrifugation,and the concentration of the dissolved compound is determined by UVspectroscopy or high-pressure liquid chromatography (HPLC) using anappropriate calibration curve.

1. Compounds of the general formula (I)

in which R1 is ethoxy; R2 is hydrogen; R3 is cyano; R4 is hydrogen; R5is hydrogen, methoxy or ethoxy; R6 is hydrogen or methoxy; R7 ishydrogen, methyl, ethyl, n-propyl or isopropyl; X1 is —NH—; X2 is N orCH; X3 is N or CH; where X2 and X3 are not simultaneously N; and thepharmaceutically acceptable salts, tautomeric forms and prodrugsthereof.
 2. Compounds according to claim 1, in which R5 is hydrogen ormethoxy.
 3. Compounds according to claim 1, in which R7 is hydrogen,methyl or ethyl.
 4. Compounds according to any of claims 1 to 3, inwhich R5 is hydrogen or methoxy; R7 is hydrogen, methyl or ethyl; X1 is—NH—; X2 is N; and X3 is CH.
 5. Compounds according to any of claims 1to 3, in which R5 is hydrogen or methoxy; R7 is hydrogen, methyl orethyl; X1 is —NH—; X2 is CH; and X3 is N.
 6. Compounds according to anyof claims 1 to 3, in which R5 is methoxy; R6 is methoxy R7 is methyl orethyl; X1 is —NH—; X2 is CH and X3 is Nor X2 is N and X3 is CH. 7.Compounds according to any of claims 1 to 3, in which R5 is methoxy; R6is methoxy; R7 is methyl; X1 is —NH—; X2 is N; and X3 is CH. 8.Compounds according to any of claims 1 to 3, in which R5 is methoxy; R6is methoxy; R7 is methyl; X1 is —NH—; X2 is CH; and X3 is N. 9.Compounds according to any of claims 1 to 3, in which R5 is methoxy; R6is methoxy; R7 is ethyl; X1 is —NH—; X2 is CH; and X3 is N. 10.Compounds of the general formula (I) according to any of claims 1 to 9,characterized in that they are present in optically active form and thatthey are the (laevorotatory) (−)-enantiomer, which rotates the plane ofpolarization of linear polarized light to the left, of the compound ofthe general formula (I) in question in the form of the free base, andthe pharmaceutically acceptable salts, tautomeric forms and/or prodrugsthereof.
 11. Compounds of the general formula (I) according to any ofclaims 1 to 9, characterized in that they are present in opticallyactive form, where the absolute configuration of the chiral C-3 ringcarbon atom corresponds to the absolute configuration at C-3 of the(laevorotatory) (−)-enantiomer, which rotates the plane of polarizationof linear polarized light to the left, of the compound of the formula(Ia) in the form of the free base

and the pharmaceutically acceptable salts, tautomeric forms and prodrugsthereof.
 12. Compounds of the general formula (I) according to claim 10in optically active form, characterized in that the correspondinglaevorotatory (−)-enantiomer is present in an optical purity(enantiomeric excess, ee) of greater than 50%, and the pharmaceuticallyacceptable salts, tautomeric forms and prodrugs thereof.
 13. Compoundsof the general formula (I) according to claim 11 in optically activeform, characterized in that the enantiomer having the preferred absoluteconfiguration at the C-3 ring carbon atom is present in an opticalpurity (enantiomeric excess, ee) of greater than 50%, and thepharmaceutically acceptable salts, tautomeric forms and prodrugsthereof.
 14. Compounds of the general formula (I) according to claim 10in optically active form, characterized in that the correspondinglaevorotatory (−)-enantiomer is present in an optical purity(enantiomeric excess, ee) of greater than 90%, and the pharmaceuticallyacceptable salts, tautomeric forms and prodrugs thereof.
 15. Compoundsof the general formula (I) according to claim 11 in optically activeform, characterized in that the enantiomer having the preferred absoluteconfiguration at the C-3 ring carbon atom is present in an opticalpurity (enantiomeric excess, ee) of greater than 90%, and thepharmaceutically acceptable salts, tautomeric forms and prodrugsthereof.
 16. Compounds of the general formula (I) according to any ofclaims 1 to 9 in the form of the racemate, and the pharmaceuticallyacceptable salts, tautomeric forms and prodrugs of the racemate of thecompounds of the general formula (I).
 17. Medicament, comprising atleast one compound of the general formula (I) according to any of claims1 to 16 or at least one pharmaceutically acceptable salt, one tautomericform or one prodrug thereof.
 18. At least one compound of the generalformula (I) according to any of claims 1 to 16, or at least onepharmaceutically acceptable salt, one tautomeric form or one prodrugthereof for use as a medicament.
 19. Use of at least one compound of thegeneral formula (I) according to any of claims 1 to 16 or at least onepharmaceutically acceptable salt, one tautomeric form or one prodrugthereof for the treatment and/or prophylaxis of at least onevasopressin-dependent disease.
 20. Use of at least one compound of thegeneral formula (I) according to any of claims 1 to 16 or at least onepharmaceutically acceptable salt, one tautomeric form or one prodrugthereof for the treatment and/or prophylaxis of at least one disorderselected from the group consisting of diabetes, insulin resistance,nocturnal enuresis, incontinence, diseases in which blood coagulationdisorders occur, and/or for delaying micturition.
 21. Use of at leastone compound of the general formula (I) according to any of claims 1 to16 or at least one pharmaceutically acceptable salt, one tautomeric formor one prodrug thereof for the treatment and/or prophylaxis of at leastone disorder selected from the group consisting of hypertension,pulmonary hypertension, heart failure, myocardial infarction, coronaryspasm, unstable angina, PTCA (percutaneous transluminal coronaryangioplasty), ischemias of the heart, disorders of the renal system,edemas, renal vasospasm, necrosis of the renal cortex, hyponatremia,hypokalemia, Schwartz-Bartter syndrome, disorders of thegastrointestinal tract, gastritic vasospasm, hepatocirrhosis, gastricand intestinal ulcer, emesis, emesis occurring during chemotherapy,and/or travel sickness.
 22. Use of at least one compound of the generalformula (I) according to any of claims 1 to 16 or at least onepharmaceutically acceptable salt, one tautomeric form or one prodrugthereof for the treatment of affective disorders.
 23. Use of at leastone compound of the general formula (I) according to any of claims 1 to16 or at least one pharmaceutically acceptable salt, one tautomeric formor one prodrug thereof for the treatment of anxiety disorders and/orstress-dependent anxiety disorders.
 24. Use of at least one compound ofthe general formula (I) according to any of claims 1 to 16 or at leastone pharmaceutically acceptable salt, one tautomeric form or one prodrugthereof for the treatment of memory impairments and/or Alzheimer'sdisease.
 25. Use of at least one compound of the general formula (I)according to any of claims 1 to 16 or at least one pharmaceuticallyacceptable salt, one tautomeric form or one prodrug thereof for thetreatment of psychoses and/or psychotic disorders.
 26. Use of at leastone compound of the general formula (I) according to any of claims 1 to16 or at least one pharmaceutically acceptable salt, one tautomeric formor one prodrug thereof for the treatment of Cushing's syndrome or otherstress-dependent diseases.
 27. Use of at least one compound of thegeneral formula (I) according to any of claims 1 to 16 or at least onepharmaceutically acceptable salt, one tautomeric form or one prodrugthereof for the treatment of sleep disorders.
 28. Use of at least onecompound of the general formula (I) according to any of claims 1 to 16or at least one pharmaceutically acceptable salt, one tautomeric form orone prodrug thereof for the treatment of depressive disorders
 29. Useaccording to claim 28, for the treatment and/or prophylaxis of childhoodonset mood disorders.
 30. Use of at least one compound of the generalformula (I) according to any of claims 1 to 16 or at least onepharmaceutically acceptable salt, one tautomeric form or one prodrugthereof for the treatment of vasomotor symptoms and/or thermoregulatorydysfunctions, such as, for example, the “hot flush” symptom.
 31. Use ofat least one compound of the general formula (I) according to any ofclaims 1 to 16 or at least one pharmaceutically acceptable salt, onetautomeric form or one prodrug thereof for the treatment and/orprophylaxis of drug dependencies, medicament dependencies and/ordependencies mediated by other factors, for the treatment and/orprophylaxis of stress caused by the withdrawal of one or more factorsmediating the dependency and/or for the treatment and/or prophylaxis ofstress-induced relapses into the drug dependencies, medicamentdependencies and/or dependencies mediated by other factors.
 32. Use ofat least one compound of the general formula (I) according to any ofclaims 1 to 16 or at least one pharmaceutically acceptable salt, onetautomeric form or one prodrug thereof for the treatment and/orprophylaxis of schizophrenia and/or psychosis.
 33. Method for thetreatment and/or prophylaxis of at least one disorder selected from thegroup consisting of diabetes, insulin resistance, nocturnal enuresis,incontinence, diseases in which blood coagulation disorders occur, andfor delaying micturition in a patient, characterized in that aneffective amount of at least one compound of the general formula (I)according to any of claims 1 to 16 or at least one pharmaceuticallyacceptable salt, one tautomeric form or one prodrug thereof isadministered to the patient.
 34. Method for the treatment and/orprophylaxis of at least one disorder selected from the group consistingof hypertension, pulmonary hypertension, heart failure, myocardialinfarction, coronary spasm, unstable angina, PTCA (percutaneoustransluminal coronary angioplasty), ischemias of the heart, disorders ofthe renal system, edemas, renal vasospasm, necrosis of the renal cortex,hyponatremia, hypokalemia, Schwartz-Bartter syndrome, disorders of thegastrointestinal tract, gastritic vasospasm, hepatocirrhosis, gastricand intestinal ulcer, emesis, emesis occurring during chemotherapy, andtravel sickness in a patient, characterized in that an effective amountof at least one compound of the general formula (I) according to any ofclaims 1 to 16 or at least one pharmaceutically acceptable salt, onetautomeric form or one prodrug thereof is administered to the patient.35. Method for the treatment and/or prophylaxis of affective disordersin a patient, characterized in that an effective amount of at least onecompound of the general formula (I) according to any of claims 1 to 16or at least one pharmaceutically acceptable salt, one tautomeric form orone prodrug thereof is administered to the patient.
 36. Method for thetreatment of anxiety disorders and/or stress-dependent anxiety disordersin a patient, characterized in that an effective amount of at least onecompound of the general formula (I) according to any of claims 1 to 16or at least one pharmaceutically acceptable salt, one tautomeric form orone prodrug thereof is administered to the patient.
 37. Method for thetreatment of memory impairments and/or Alzheimer's disease in a patient,characterized in that an effective amount of at least one compound ofthe general formula (I) according to any of claims 1 to 16 or at leastone pharmaceutically acceptable salt, one tautomeric form or one prodrugthereof is administered to the patient.
 38. Method for the treatment ofpsychoses and/or psychotic disorders in a patient, characterized in thatan effective amount of at least one compound of the general formula (I)according to any of claims 1 to 16 or at least one pharmaceuticallyacceptable salt, one tautomeric form or one prodrug thereof isadministered to the patient.
 39. Method for the treatment of Cushing'ssyndrome in a patient, characterized in that an effective amount of atleast one compound of the general formula (I) according to any of claims1 to 16 or at least one pharmaceutically acceptable salt, one tautomericform or one prodrug thereof is administered to the patient.
 40. Methodfor the treatment of sleep disorders in a patient, characterized in thatan effective amount of at least one compound of the general formula (I)according to any of claims 1 to 16 or at least one pharmaceuticallyacceptable salt, one tautomeric form or one prodrug thereof isadministered to the patient.
 41. Method for the treatment of depressivedisorders in a patient, characterized in that an effective amount of atleast one compound of the general formula (I) according to any of claims1 to 16 or at least one pharmaceutically acceptable salt, one tautomericform or one prodrug thereof is administered to the patient.
 42. Methodaccording to claim 41, for the treatment and/or prophylaxis of childhoodonset mood disorders.
 43. Method for the treatment and/or prophylaxis ofvasomotor symptoms and/or thermoregulatory dysfunctions, such as, forexample, the “hot flush” symptom, in a patient, characterized in that aneffective amount of at least one compound of the general formula (I)according to any of claims 1 to 16 or at least one pharmaceuticallyacceptable salt, one tautomeric form or one prodrug thereof isadministered to the patient.
 44. Method for the treatment and/orprophylaxis of drug dependencies, medicament dependencies and/ordependencies mediated by other factors, for the treatment and/orprophylaxis of stress caused by the withdrawal of one or more factorsmediating the dependency and/or for the treatment and/or prophylaxis ofstress-induced relapses in the drug dependencies, medicamentdependencies and/or dependencies mediated by other factors, in apatient, characterized in that an effective amount of at least onecompound of the general formula (I) according to any of claims 1 to 16or at least one pharmaceutically acceptable salt, one tautomeric form orone prodrug thereof is administered to the patient.
 45. Method for thetreatment and/or prophylaxis of schizophrenia and/or psychosis in apatient, characterized in that an effective amount of at least onecompound of the general formula (I) according to any of claims 1 to 16or at least one pharmaceutically acceptable salt, one tautomeric form orone prodrug thereof is administered to the patient.
 46. Method accordingto any of claims 33 to 45, characterized in that the patient is amammal, preferably a human or a nonhuman or a nonhuman transgenicmammal.
 47. Process for preparing at least one compound of the generalformula (I) according to any of claims 1 to 16, characterized in that itcan be prepared by the relevant skilled worker with knowledge of thetechnical teaching of the invention in implementation and/or inanalogous implementation of process steps known per se.
 48. A compoundof the formula (I) according to any of claims 1 to 7, or apharmaceutically acceptable salt, a tautomeric form or a prodrug thereoffor use in treatment and/or prophylaxis of a disease or disorder. 49.The compound as claimed in claim 48 for use in treatment and/orprophylaxis of a disease or disorder as set forth in any of claims 19 to32.
 50. Use of the compound of the formula (I) according to any ofclaims 1 to 7 or at least one pharmaceutically acceptable salt, onetautomeric form or one prodrug thereof for the manufacture of amedicament for the treatment and/or prophylaxis of a disease ordisorder.
 51. The use as claimed in claim 50, where the disease ordisorder is as set forth in any of claims 19 to 32.